Uses of 2-(1H-indolylsulfanyl)-benzyl amine derivatives as SSRIS

ABSTRACT

The present invention relates to uses of 2-(1H-indolylsulfanyl)-benzyl amine derivatives of general formula (I): 
                         
in the treatment of affective disorders.

Under 35 U.S.C. §120, this application is a divisional of U.S. Ser. No.11/314,702, filed Dec. 21, 2005, which is §365(c) continuation of PCTInternational Application No. PCT/DK2004/000894, filed Dec. 21, 2004,which claims the benefit of priority under 35 U.S.C. §119(e) of U.S.Provisional Application No. 60/532,593, filed Dec. 23, 2003, and under35 U.S.C. §119(a)-(d), claims benefit of Danish Application No.PA200301923, filed Dec. 23, 2003. The entirety of each aforementionedapplication is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds which are serotonin reuptakeinhibitors and preferably also norepinephrine reuptake inhibitors, andthe medical use of such compounds, e.g. in the treatment of depressionand anxiety, affective disorders, pain disorders, attention deficithyperactivity disorder (ADHD) and stress urinary incontinence.

BACKGROUND OF THE INVENTION

The majority of currently available antidepressants can be classified in3 classes:

-   -   1) monoamine oxidase inhibitors (MAOIs),    -   2) biogenic amine neurotransmitter [serotonin (5-HT),        norepinephrine (NE) and dopamine (DA)] transporter reuptake        blockers, and    -   3) modulators, especially blockers of one or more of the 5-HT        and/or NE receptors.

Since depression is associated with a relative deficiency of thebiogenic amines, the use of 5-HT and/or NE-receptor blockers (i.e. 5-HTand or NE-antagonist's) have not proven very successful in the treatmentof depression and anxiety and the preferred and currently most efficienttreatments are based on the enhancement of 5-HT and/or NEneurotransmission by blocking their reuptake back from the synapticcleft (Slattery, D. A. et al., “The evolution of antidepressantmechanisms”, fundamental and Clinical pharmacology, 2004, 18, 1-21;Schloss, P. et al, “new insights into the mechanism of antidepressanttherapy”, Pharmacology and therapeutics, 2004, 102, 47-60).

For years monoamine reuptake inhibition has been studied for treatmentof depression, i.e. in particular the monoamines serotonin (5-HT),norepinephrine (NE) and dopamine (DA).

Selective serotonin reuptake inhibitors (hereinafter referred to asSSRIs) have become first choice therapeutics in the treatment ofdepression, certain forms of anxiety and social phobias, because theygenerally are effective, well tolerated, and have a favourable safetyprofile compared to the classic tricyclic antidepressants. Drugs claimedto be SSRIs are for example fluoxetine, sertraline and paroxetine.

However, clinical studies on depression indicate that non-response tothe known SSRIs is substantial, up to 30%. Another, often neglected,factor in antidepressant treatment is compliance, which has a ratherprofound effect on the patient's motivation to continue pharmacotherapy.First of all, there is generally a delay in therapeutic effect of theSSRIs. Sometimes symptoms even worsen during the first weeks oftreatment. Secondly, sexual dysfunction is generally a side effectcommon to SSRIs. Without addressing these problems, real progress in thepharmacotherapy of depression and anxiety disorders is not likely tohappen. Accordingly, there is a need for the development of compoundscapable of improving the treatment of depression and other serotoninrelated diseases.

A newer strategy has been the development of dual re-uptake inhibitors,e.g., the combined effect of serotonin reuptake inhibition andnorepinephrine (norepinephrine is also named noradrenaline, NA) reuptakeinhibition on depression is explored in clinical studies of compoundssuch as Duloxetine (Wong, “Duloxetine (LY-248686): an inhibitor ofserotonin and noradrenaline uptake and an antidepressant drugcandidate”, Expert Opinion on Investigational Drugs, 1998, 7, 10,1691-1699) and Venlafaxine (Khan-A et al, 30 “Venlafaxine in depressedoutpatients”, Psychopharmacology Bulletin, 1991, 27, 141-144). Compoundshaving such duel effect are also named SNRIs, “serotonin andnoradrenaline reuptake inhibitors”, or NSRIs, “noradrenaline andserotonin reuptake inhibitors”.

Since treatment with the selective NE reuptake inhibitor reboxetine hasbeen shown to stimulate 5-HT neurons and mediate the release of 5-HT inthe brain (Svensson, T. et al, J. Neural. Transmission, 2004, 111, 127)there might be a synergistic advantage using SNRI's in the treatment ofdepression or anxiety.

The use of SNRI's have been shown in clinical studies to have abeneficial effect on pain (e.g. Fibromyalgia syndrome, overall pain,back pain, shoulder pain, headache, pain while awake and during dailyactivities) and especially pain associated with depression (Berk, M.Expert Rev. Neurotherapeutics 2003, 3, 47-451; Fishbain, D. A., et al.“Evidence-based data from animal and human experimental studies on painrelief with antidepressants: A structured review” Pain Medicine 20001:310-316).

SNRI's have also been shown in clinical studies to have a beneficialeffect in attention deficit hyperactivity disorder (ADHD) (N. M.Mukaddes; Venlafaxine in attention deficit hyperactivity disorder,European Neuropsychopharmacology, Volume 12, Supplement 3, October 2002,Page 421).

Furthermore, SNRI's have been shown to be effective for the treatment ofstress urinary incontinence (Dmochowski R. R. et al. “Duloxetine versusplacebo for the treatment of North American women with stress urinaryincontinence”, Journal of Urology 2003, 170:4, 1259-1263.)

Furthermore, Axford L. et al. describe the development of triple 5-HT,NE and DA re-uptake inhibitors for treatment of depression. (2003,Bioorganic & Medical Chemistry Letters, 13, 3277-3280:“Bicyclo[2.2.1.]heptanes as novel triple re-uptake inhibitors for thetreatment of depression”). Wellbutrin (bupropion) which has DA re-uptakeactivity in vitro and in vivo, show antidepressant efficacy. Othercombination studies have indicated that addition of some affininity atthe DA uptake site may have some clinical benefit (Nelson, J. C. J.Clin. Psychiatry 1998, 59, 65; Masand, P. S. et al. Depression Anxiety1998, 7, 89; Bodkin, J. A et al. J. Clin. Psychiatry 1997, 58, 137).

The present invention provides 2-(1H-indolylsulfanyl)-benzyl aminederivatives, formula I, which are serotonin reuptake inhibitors. Inparticular, the invention provides compounds possessing the combinedeffect of serotonin reuptake inhibition and norepinephrine reuptakeinhibition. Furthermore, some of the compounds are also triple 5-HT, NEand DA re-uptake inhibitors.

Diphenyl sulphides of formula (XVI) and variations thereof have beendisclosed as serotonin re-uptake inhibitors and have been suggested foruse in treatment of depression, cf. e.g. U.S. Pat. No. 5,095,039, U.S.Pat. No. 4,056,632, EP 396827 A1 and WO 9312080. EP 402097 describeshalogen substituted diphenylsulfides claimed to be selective serotonininhibitors for treatment of depression. Likewise WO 9717325 disclosesderivatives of N,N-dimethyl-2-(arylthio)benzylamine claimed to beselective serotonin transport inhibitors and suggest their use asantidepressants. J. Jilek et al., 1989, Collect. Czeck Chem. Commun.,54, 3294-3338 also discloses various derivatives of diphenyl sulphides,“phenyl-thio-benzylamines” as antidepressants. Furthermore, diphenylsulphides are also disclosed in U.S. Pat. No. 3,803,143 and claimeduseful as antidepressant.

Several publications relates to the use of derivatives of diphenylsulphides as “radiopharmaceuticals” for imaging SERT by SPECT or PETimaging, e.g. “S. Oya et al. J. Med. Chem. 2002, 45, 4716-4723” and “S.Oya et al. J. Med. Chem. 42, 3, 333-335”. P. Emond et al (J. Med. Chem.(2002) 45, 1253-1258) and “S. Oya et al. (J. Med. Chem. 42, 3, 333-335)further test and discuss substituted “diphenyl sulfides” as selectiveserotonin tranporter ligands relative to dopamine and norepinephrinetransporters (DAT, NET) with measurements of vitro affinities at thedopamine, serotonin, and norepinephrine transporters.

WO 0066537 also discloses certain derivatives of diphenyl sulphidesclaimed to be have higher selectivity for SERT over NET and DAT.

U.S. Pat. No. 4,018,830 and U.S. Pat. No. 4,055,665 discloses“phenylthioaralkylamines” and “2-phenylthiobenzylamines” representedstructurally as “Ar₁-S—Ar₂ in which Ar₁ is a phenylakyl aminesubstituent and Ar₂ is a substituted or unsubstituted homocyclic orheterocyclic ring off from 5-6 atoms, such as an aromatic ring, aheteroaromatic ring”. The compounds are claimed to be useful forpreventing “cardiac arrhythmias”.

K. Sindelar et al., “Collection of Czechoslovak Chemical Communications,(1991), 56(2), 449-58, by K. Sindelar et al” disclose variations ofcompounds of formula (XVI) in which one of the rings is substituted witha thiophene ring with test for selectivity as 5-HT re-uptake inhibitorand NA re-uptake inhibitor, respectively, for use as antidepressants.

U.S. Pat. No. 6,596,741 B2 and U.S. Pat. No. 6,436,938 B1 and U.S. Pat.No. 6,410,736 B1 disclose biaryl ether derivates (XVII) reported toinhibit reuptake of monoamines, e.g. serotonin, dopamine and/ornorepinephrine.

None of the above references disclose compounds comprising an indolegroup like the indolyl-sulfanyl benzyl amines of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to a compound having the general formula I

wherein the sulphur atom is attached to the indole via any ring carbonof the indole and wherein R¹-R¹³ are as defined below;

as the free base or a salt thereof.

In a further aspect the invention provides a compound of the aboveformula I according to the above as the free base or a pharmaceuticalacceptable salt thereof for use as a medicament.

The invention also provides a pharmaceutical composition comprising acompound according to the above as the free base or a pharmaceuticallyacceptable salt thereof and at least one pharmaceutically acceptablecarrier or diluent.

The invention further provides a method for the treatment of anaffective disorder, such as depression, anxiety disorders includinggeneral anxiety disorder, social anxiety disorder, post traumatic stressdisorder, obsessive compulsive disorder, panic disorder, panic attacks,specific phobias, social phobia or agoraphobia in a living animal body,including a human, comprising administering a therapeutically effectiveamount of a compound according to the above as the free base or a saltsuch as a pharmaceutically acceptable salt thereof. The inventionfurthermore concerns the use of a compound according to the above in amethod of treatment of pain disorders, ADHD and stress urinaryincontinence.

The invention further provides the use of a compound according to theabove as the free base or a salt such as a pharmaceutically acceptablesalt thereof for the preparation of a pharmaceutical composition for thetreatment an affective disorder, such as depression, anxiety disordersincluding general anxiety disorder, social anxiety disorder, posttraumatic stress disorder, obsessive compulsive disorder, panicdisorder, panic attacks, specific phobias, social phobia or agoraphobia.The invention furthermore provides the use of a compound according tothe above for the preparation of a pharmaceutical composition for thetreatment of pain disorders, ADHD and stress urinary incontinence.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “halogen” means fluoro, chloro, bromo or iodo. “Halo” meanshalogen.

The expression “C₁₋₆-alk(en/yn)yl” means a C₁₋₆-alkyl, a C₂₋₆-alkenyl ora C₂₋₆-alkynyl group.

The term “C₁₋₆ alkyl” refers to a branched or unbranched alkyl grouphaving from one to six carbon atoms inclusive, including but not limitedto methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl and 2-methyl-1-propyl. Similarly, the term “C₁₋₄alkyl” refers to a branched or unbranched alkyl group having from one tosix carbon atoms inclusive, including but not limited to methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and2-methyl-1-propyl.

The term “C₂₋₆ alkenyl” designate such groups having from two to sixcarbon atoms, including one double bond, including but not limited toethenyl, propenyl, and butenyl.

The term “C₂₋₆ alkynyl” designate such groups having from two to sixcarbon atoms, including one triple bond, including but not limited toethynyl, propynyl and butynyl.

The expression “C₃₋₈-cycloalk(en)yl” means a C₃₋₈-cycloalkyl or aC₃₋₈-cycloalkenyl group.

The term “C₃₋₈-cycloalkyl” designates a monocyclic or bicycliccarbocycle having three to eight C-atoms, including but not limited tocyclopropyl, cyclopentyl, and cyclohexyl.

The term “C₃₋₈-cycloalkenyl” designates a monocyclic or bicycliccarbocycle having three to eight C-atoms and one double bond, includingbut not limited to cyclopropenyl, cyclopentenyl and cyclohexenyl.

In the expression “C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl”, the terms“C₃₋₈-cycloalk(en)yl” and “C₁₋₆-alk(en/yn)yl” are as defined above.

The term “C₁₋₆-alk(en/yn)yloxy” refers to groups of the formulaC₁₋₆-alk(en/yn)yl-O—, wherein C₁₋₆-alk(en/yn)yl are as defined above.

The terms “C₁₋₆-alk(en/yn)yl-carbonyl”,“C₁₋₆-alk(en/yn)yl-aminocarbonyl” and“di-(C₁₋₆-alk(en/yn)yl)aminocarbonyl” refers to groups of formulaC₁₋₆-alk(en/yn)yl-CO—, C₁₋₆-alk(en/yn)yl-NH—CO— and(C₁₋₆-alk(en/yn)yl)₂-N—CO—, respectively, wherein C₁₋₆-alk(en/yn)yl areas defined above.

In the expressions “C₁₋₆-alk(en/yn)yl-amino”, “di-(C₁₋₆-alkyl)amino”,“C₁₋₆-alk(en/yn)ylthio”, “halo-C₁₋₆-alk(en/yn)yl”,“halo-C₁₋₆-alk(en/yn)yl-sulfonyl”, “halo-C₁₋₆-alk(en/yn)yl-sulfanyl”,“C₁₋₆-alk(en/yn)ylsulfonyl”, and “C₁₋₆-alk(en/yn)ylsulfanyl” etc., theterms “C₁₋₆-alk(en/yn)yl” and “halo” are as defined above.

The expression “R¹ and R² together with the nitrogen form a 4-7 memberedring containing zero or one double bond, optionally said ring inaddition to said nitrogen comprises one further heteroatom selected fromnitrogen, oxygen and sulphur” refers to a heterocylic rings system of atotal of 4, 5, 6 or 7 members, such as, e.g. azetidine, pyrrolidine,piperidine, piperazine, homopiperazine or morpholine. This rings systemmay be unsubstituted or it may comprise one or more substituents, suchas, e.g. a maximum of one or two substituents, e.g. selected from thegroup consisting halogen, hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, alkylsulphonyl, trifluoromethyl,trifluoromethylsulfonyl, and C₁₋₆-alkylcarbonyl.

The atoms of the indole are numbered according to IUPAC Commission onNomenclature of Organic Chemistry guidelines (Rigaudy, J.; Klesney, S.P. Nomenclature of Organic Chemistry Pergamon Press, (1979) ISBN0080223699).

The term “treatment” as used herein in connection with a disease ordisorders includes also prevention as the case may be.

Compounds of the Invention

The present invention relates to a compound having the general formula I

wherein the sulphur atom is attached to the indole via any ring carbonof the indole and wherein

-   -   R¹-R² are independently selected from hydrogen,        C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, and        C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl or R¹ and R² together with        the nitrogen form a 4-7 membered ring containing zero or one        double bond, optionally said ring in addition to said nitrogen        comprises one further heteroatom selected from nitrogen, oxygen        and sulphur;    -   R³-R¹² are independently selected from hydrogen, halogen, cyano,        nitro, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,        C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,        C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,        C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,        C₁₋₆-alk(en/yn)ylaminocarbonyl,        di-(C₁₋₆-alk(en/yn)yl)aminocarbonyl, hydroxy,        C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk(en/yn)ylthio,        halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)ylsulfonyl,        halo-C₁₋₆-alk(en/yn)ylsulfanyl and C₁₋₆-alk(en/yn)ylsulfonyl;        and    -   R¹³ is selected from hydrogen, C₁₋₆-alk(en/yn)yl,        C₃₋₈-cycloalk(en)yl and C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;

as the free base or a salt thereof;

with the provisos that:

-   -   when the sulphur atom is attached via atom nr. 2 of the indole        then R⁷ does not exist;    -   when the sulphur atom is attached via atom nr. 3 of the indole        then R¹² does not exist;    -   when the sulphur atom is attached via atom nr. 4 of the indole        then R⁸ does not exist;    -   when the sulphur atom is attached via atom nr. 5 of the indole        then R⁹ does not exist;    -   when the sulphur atom is attached via atom nr. 6 of the indole        then R¹⁰ does not exist; and    -   when the sulphur atom is attached via atom nr. 7 of the indole        then R¹¹ does not exist.

To further illustrate the invention, without limitation, the followingembodiments of R¹-R² are within the scope of the invention, inparticular for the compounds of the invention as the free base and thesalts thereof:

-   R¹-R² are independently selected from hydrogen, C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yl and C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;-   R¹-R² are independently selected from hydrogen and C₁₋₆-alkyl;-   R¹-R² are independently selected from hydrogen and C₁₋₄-alkyl;-   R¹ is hydrogen and R² is methyl;-   R¹ and R² are methyl;-   R¹ and R² are hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of R¹-R² are within the scope of the invention, inparticular for the compounds of the invention as the free base and thesalts thereof:

-   R¹-R² are independently selected from hydrogen and    C₁₋₆-alk(en/yn)yl; or R¹ and R² together with the nitrogen form a    4-7 membered ring containing zero or one double bond, optionally the    ring in addition to the nitrogen comprises one further heteroatom    selected from nitrogen, oxygen and sulphur.

To further illustrate the invention, without limitation, the followingembodiments of R¹-R² are also within the scope of the invention, inparticular for the compounds of the invention as the free base and thesalts thereof:

R¹ and R² together with the nitrogen form a 4-7, i.e. including 5 or 6,membered ring containing zero or one double bond, optionally said ringin addition to said nitrogen comprises one further heteroatom selectedfrom nitrogen, oxygen and sulphur, which ring system is unsubstituted;

R¹ and R² together with the nitrogen form a 4-7, including 5 or 6,membered ring containing zero or one double bond, optionally said ringin addition to said nitrogen comprises one further heteroatom selectedfrom nitrogen, oxygen and sulphur, which ring system comprises one ormore substituents, such as, e.g. a maximum of one or two substituents,e.g. selected from the group consisting of hydroxy, C₁₋₆-alkyl (e.g.methyl), halogen (e.g. fluoro or chloro), C₁₋₆-alkoxy (e.g. methoxy),C₁₋₆-alkylthio, alkylsulphonyl, trifluoromethyl, trifluoromethylsulfonyland C₁₋₆-alkylcarbonyl;

R¹ and R² together with the nitrogen form a ring selected from the groupconsisting of azetidine, pyrrolidine, piperidine, piperazine,homopiperazine or morpholine, which ring may be unsubstituted or it maycomprise one or more substituents, such as, e.g. a maximum of one or twosubstituents, e.g. selected from the group consisting of hydroxy,C₁₋₆-alkyl (e.g. methyl), halogen (e.g. fluoro or chloro), C₁₋₆-alkoxy(e.g. methoxy), C₁₋₆-alkylthio, alkylsulphonyl, trifluoromethyl,trifluoromethylsulfonyl and C₁₋₆-alkylcarbonyl.

To further illustrate the invention, without limitation, the followingembodiments of R³-R¹² are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R³-R¹² are independently selected from hydrogen, halogen, cyano,    C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,    C₁₋₆-alkyloxy, C₁₋₆-alkylthio and trifluoromethyl;-   R³-R¹² are independently selected from hydrogen, chloro, fluoro,    cyano, methyl, methoxy, methylthio and trifluoromethyl;-   R³-R¹² are hydrogen;-   R³-R¹² are independently selected from hydrogen and halogen;-   R³-R¹² are independently selected from hydrogen, chloro and fluoro;-   R³-R¹² are independently selected from hydrogen and chloro;-   R³-R¹² are independently selected from hydrogen and fluoro; at least    one of R³-R¹² is fluoro or chloro;-   R³-R¹² are selected independently from hydrogen and cyano;-   R³-R¹² are selected independently from hydrogen and    C₁₋₆-alk(en/yn)yl;-   R³-R¹² are selected independently from hydrogen and C₁₋₆-alkyl, such    as methyl;-   R³-R¹² are selected independently from hydrogen and    C₁₋₆-alk(en/yn)yloxy, preferably C₁₋₆-alkoxy, such as methoxy;-   R³-R¹² are selected independently from hydrogen and C₁₋₆-alkylthio,    such as methylthio;-   R³-R¹² are selected independently from hydrogen and trifluoromethyl.

Within the invention, are embodiments where:

-   a limited number of R³-R¹² are different from hydrogen, e.g. at    least 3, or at least 5 or at least 6 of R³-R¹² are hydrogen;-   all of R³-R¹² are hydrogen;-   only 1, 2, 3 or 4 of R³-R¹² is different from hydrogen.

In one embodiment of the invention only 1, 2 or 3 of R³-R¹² aredifferent from hydrogen, preferably selected independently from thegroup consisting of hydrogen, chloro, fluoro, cyano, methyl, methoxy,methylthio and trifluoromethyl.

To further illustrate the invention, without limitation, the followingembodiments of R³-R¹² are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R³-R¹² are independently selected from hydrogen, halogen, cyano,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, hydroxy, C₁₋₆-alk(en/yn)yloxy    and halo-C₁₋₆-alk(en/yn)yl;-   R³-R¹² are independently selected from hydrogen, halogen, cyano,    C₁₋₆-alk(en/yn)yl, hydroxy, C₁₋₆-alk(en/yn)yloxy and    halo-C₁₋₆-alk(en/yn)yl; one of R³-R¹² is halogen such as chloro or    bromo or iodo or fluoro;-   one of R³-R¹² is cyano;-   one of R³-R¹² is C₁₋₆-alk(en/yn)yl, such as C₁₋₆-alkyl, e.g. methyl    or ethyl;-   one of R³-R¹² is hydroxy;-   one of R³-R¹² is C₁₋₆-alk(en/yn)yloxy, such as C₁₋₆-alkyloxy, e.g.    methoxy;-   one of R³-R¹² is halo-C₁₋₆-alk(en/yn)yl such as halo-C₁₋₆-alkyl,    e.g. trifluoro-methyl.

Within the invention, are embodiments where:

-   one of R³-R¹² is different from hydrogen;-   two of R³-R¹² are different from hydrogen;-   three of R³-R¹² are different from hydrogen;-   four of R³-R¹² are different from hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of R³-R⁶ are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R³-R⁶ are independently selected from hydrogen, halogen, cyano,    nitro, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,    C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,    C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,    C₁₋₆-alk(en/yn)ylaminocarbonyl, di-(C₁₋₆-alk(en)yl)aminocarbonyl,    hydroxy, C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk(en/yn)ylthio,    halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)ylsulfonyl,    halo-C₁₋₆-alk(en/yn)ylsulfanyl and C₁₋₆-alk(en/yn)ylsulfonyl;-   R³-R⁶ are independently selected from hydrogen, halogen, cyano,    C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,    C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,    aminocarbonyl, C₁₋₆-alkylaminocarbonyl,    di-(C₁₋₆-alkylamino)carbonyl, hydroxy, C₁₋₆-alkoxy, C₁₋₆-alkylthio,    halo-C₁₋₆-alkyl, halo-C₁₋₆-alkylsulfonyl, halo-C₁₋₆-alkylsulfanyl    and C₁₋₆-alkylsulfonyl;-   R³-R⁶ are independently selected from hydrogen, halogen,    C₁₋₆-alkyloxy and C₁₋₆-alkyl;-   R³-R⁶ are independently selected from hydrogen, halogen, methoxy and    methyl;-   R³-R⁶ are independently selected from hydrogen, fluoro, chloro,    methoxy and methyl.

Within the invention, are embodiments where a limited number of R³-R⁶are different from hydrogen, e.g.:

-   only one or two of R³-R⁶ is different from hydrogen;-   three of R³-R⁶ are hydrogen and one of R³-R⁶ is halogen;-   three of R³-R⁶ are hydrogen and one of R³-R⁶ is methyl;-   R⁴ is different from hydrogen;-   R⁵ is different from hydrogen;-   R⁴ is different from hydrogen, e.g. chloro, fluoro, methyl or    methoxy, and the rest of R³-R⁶ is hydrogen;-   R⁵ is different from hydrogen, e.g. chloro, fluoro, methyl or    methoxy, and the rest of R³-R⁶ is hydrogen;-   only one of R³-R⁶ is different from hydrogen and is selected from    the group consisting of fluoro, chloro, methyl and methoxy;-   R³-R⁶ are hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of R³-R⁶ are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R³-R⁶ are independently selected from hydrogen, halogen, cyano,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl and    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;-   R³-R⁶ are independently selected from hydrogen, halogen and    C₁₋₆-alk(en/yn)yl;-   R³ is hydrogen;-   R⁴ is selected from hydrogen, halogen and C₁₋₆-alk(en/yn)yl;-   R⁴ is hydrogen;-   R⁴ is halogen such as chloro or fluoro;-   R⁴ is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl e.g. methyl;-   R⁵ is selected from hydrogen and halogen;-   R⁵ is hydrogen;-   R⁵ is halogen such as chloro;-   R⁶ is hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of R⁷-R¹² are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R⁷-R¹² are independently selected from hydrogen, halogen, cyano,    nitro, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,    C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,    C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,    C₁₋₆-alk(en/yn)ylaminocarbonyl, di-(C₁₋₆-alk(en)yl)aminocarbonyl,    hydroxy, C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk(en/yn)ylthio,    halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)ylsulfonyl,    halo-C₁₋₆-alk(en/yn)ylsulfanyl and C₁₋₆-alk(en/yn)ylsulfonyl.

Within the invention, are embodiments where a limited number of R⁷-R¹²are different from hydrogen, e.g.:

-   only one or two of R⁷-R¹² is different from hydrogen;-   only one of R⁷-R¹² is different from hydrogen and the substituent is    selected from the group consisting of hydrogen, methyl, fluoro,    chloro or methoxy;-   only two of R⁷-R¹² is different from hydrogen and the substituents    are selected independently from the group consisting of hydrogen,    methyl, fluoro, chloro or methoxy.

To further illustrate the invention, without limitation, the followingembodiments of R⁷-R¹² are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R⁷-R¹² are independently selected from hydrogen, halogen, cyano,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, hydroxy, C₁₋₆-alk(en/yn)yloxy    and halo-C₁₋₆-alk(en/yn)yl;-   R⁷-R¹² are independently selected from hydrogen, halogen, cyano,    C₁₋₆-alk(en/yn)yl, hydroxy, C₁₋₆-alk(en/yn)yloxy and    halo-C₁₋₆-alk(en/yn)yl;-   R⁷ is selected from hydrogen and C₁₋₆-alk(en/yn)yl;-   R⁷ is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl;-   R⁸ is selected from hydrogen, halogen, cyano, C₁₋₁₆-alk(en/yn)yl,    hydroxy and C₁₋₆-alk(en/yn)yloxy;-   R⁸ is hydrogen;-   R⁸ is halogen such as fluoro, chloro or bromo;-   R⁸ is cyano;-   R⁸ is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl e.g. methyl;-   R⁸ is hydroxy;-   R⁸ is C₁₋₆-alk(en/yn)yloxy such as C₁₋₆-alkyloxy e.g. methoxy;-   R⁹ is selected from hydrogen, halogen, cyano, C₁₋₆-alk(en/yn)yl,    hydroxy and C₁₋₆-alk(en/yn)yloxy;-   R⁹ is hydrogen;-   R⁹ is halogen such as fluoro, chloro, iodo or bromo;-   R⁹ is cyano;-   R⁹ is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl e.g. methyl;-   R⁹ is hydroxy;-   R⁹ is C₁₋₆-alk(en/yn)yloxy such as C₁₋₆-alkyloxy e.g. methoxy;-   R¹⁰ is selected from hydrogen, halogen, cyano, C₁₋₆-alk(en/yn)yl,    hydroxy, C₁₋₆-alk(en/yn)yloxy and halo-C₁₋₆-alk(en/yn)yl;-   R¹⁰ is hydrogen;-   R¹⁰ is halogen such as fluoro, chloro or bromo;-   R¹⁰ is cyano;-   R¹⁰ is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl e.g. methyl;-   R¹⁰ is hydroxy;-   R¹⁰ is C₁₋₆-alk(en/yn)yloxy such as C₁₋₆-alkyloxy e.g. methoxy;-   R¹⁰ is halo-C₁₋₆-alk(en/yn)yl such as halo-C₁₋₆-alkyl e.g.    trifluoro-methyl;-   R¹¹ is selected from hydrogen, halogen, C₁₋₆-alk(en/yn)yl and    C₁₋₆-alk(en/yn)yloxy;-   R¹¹ is hydrogen;-   R¹¹ is halogen such as fluoro or chloro;-   R¹¹ is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl e.g. methyl or ethyl;-   R¹¹ is C₁₋₆-alk(en/yn)yloxy such as C₁₋₆-alkyloxy e.g. methoxy;-   R¹² is selected from hydrogen and C₁₋₆-alk(en/yn)yl;-   R¹² is hydrogen;-   R¹² is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl e.g. methyl.

To further illustrate the invention, without limitation, the followingembodiments of R⁷ are within the scope of the invention, in particularfor the compounds as the free base or salt thereof:

-   R⁷ is hydrogen;-   R⁷ is methyl.

To further illustrate the invention, without limitation, the followingembodiments of R¹³ is within the scope of the invention, in particularfor the compounds as the free base or salt thereof:

-   R¹³ is selected from hydrogen and C₁₋₆-alk(en/yn)yl;-   R¹³ is hydrogen;-   R¹³ is C₁₋₆-alk(en/yn)yl such as C₁₋₆-alkyl e.g. methyl.

The above embodiments relates to the compounds of the invention havingformula I

In particular, the present invention relates to a compound having thegeneral formula I wherein the sulphur atom is attached to the indole asindicated in below formulas IA to IF:

and wherein R¹-R¹³ are as defined herein, in particular wherein

-   -   R¹-R² are independently selected from hydrogen,        C₁₋₆-alk(en/yn)yl (e.g. methyl), C₃₋₈-cycloalk(en)yl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or        -   R¹ and R² together with the nitrogen form a 4-7 membered            ring containing zero or one double bond, optionally the ring            in addition to the nitrogen comprises one further heteroatom            selected from nitrogen, oxygen and sulphur;    -   R³-R¹² are independently selected from hydrogen, halogen (e.g.        fluoro or chloro), cyano, nitro, C₁₋₆-alk(en/yn)yl (e.g.        C₁₋₆-alkyl, such as methyl), C₃₋₈-cycloalk(en)yl (e.g.        C₃₋₈-cycloalkyl), C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl (e.g.        C₃₋₈-cycloalkyl-C₁₋₆-alkyl), amino, C₁₋₆-alk(en/yn)ylamino (e.g.        C₁₋₆-alkylamino), di-(C₁₋₆-alk(en/yn)yl)amino (e.g.        di-(C₁₋₆-alkyl)amino), C₁₋₆-alk(en/yn)ylcarbonyl (e.g.        C₁₋₆-alkylcarbonyl), aminocarbonyl,        C₁₋₆-alk(en/yn)ylaminocarbonyl (e.g. C₁₋₆-alkylaminocarbonyl),        di-(C₁₋₆-alk(en)yl)aminocarbonyl (e.g.        di-(C₁₋₆-alkyl)aminocarbonyl)), hydroxy, C₁₋₆-alk(en/yn)yloxy        (e.g. C₁₋₆-alkoxy; such as methoxy), C₁₋₆-alk(en/yn)ylthio (e.g.        C₁₋₆-alkylthio, such as methylthio), halo-C₁₋₆-alk(en/yn)yl        (e.g., halo-C₁₋₆-alkyl, such as trifluoromethyl),        halo-C₁₋₆-alk(en/yn)ylsulfonyl (e.g. trifluoromethylsulfonyl),        halo-C₁₋₆-alk(en/yn)ylsulfanyl (e.g. trifluoromethylsulfanyl),        and C₁₋₆-alk(en/yn)ylsulfonyl (e.g. C₁₋₆-alkylsulfonyl);    -   R¹³ is selected from hydrogen, C₁₋₆-alk(en/yn)yl (e.g.        C₁₋₆-alkyl, such as methyl), C₃₋₈-cycloalk(en)yl (e.g.        C₃₋₈-cycloalkyl), and C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl        (e.g. C₃₋₈-cycloalkyl-C₁₋₆-alkyl);        as the free base or a salt thereof.

A preferred embodiment relates to the compounds of the invention havingformula IA. Any of the above embodiments are also embodiments of formulaIA with the proviso that R¹² does not exist in compounds of generalformula IA.

Another embodiment relates to the compounds of the invention which arenot of formula IA.

A further embodiment relates to the compounds of the invention havingformula IB. Any of the above embodiments are also embodiments of formulaIB with the proviso that R⁷ does not exist in compounds of generalformula IB.

Another embodiment relates to the compounds of the invention which arenot of formula IB.

A further embodiment relates to the compounds of the invention havingformula IC. Any of the above embodiments are also embodiments of formulaIC with the proviso that R⁸ does not exist in compounds of generalformula IC.

Another embodiment relates to the compounds of the invention which arenot of formula IC.

A further embodiment relates to the compounds of the invention havingformula ID. Any of the above embodiments are also embodiments of formulaID with the proviso that R⁹ does not exist in compounds of generalformula ID.

Another embodiment relates to the compounds of the invention which arenot of formula ID.

A further embodiment relates to the compounds of the invention havingformula IE. Any of the above embodiments are also embodiments of formulaIE with the proviso that R¹⁰ does not exist in compounds of generalformula IE.

Another embodiment relates to the compounds of the invention which arenot of formula IE.

A further embodiment relates to the compounds of the invention havingformula IF. Any of the above embodiments are also embodiments of formulaIF with the proviso that R¹⁰ does not exist in compounds of generalformula IF.

Another embodiment relates to the compounds of the invention which arenot of formula IF.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof: R⁸-R¹¹are independently selected from hydrogen, halogen, cyano, C₁₋₆alkyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkylamino)carbonyl, hydroxy,C₁₋₆-alkoxy, C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkylsulfonyl,halo-C₁₋₆-alkylsulfanyl, and C₁₋₆-alkylsulfonyl;

-   R⁸-R¹¹ are independently selected from hydrogen, halogen, cyano,    methyl, hydroxy, methoxy and trifluoromethyl;-   R⁸-R¹¹ are independently selected from hydrogen, halogen, methyl and    methoxy;-   R⁸-R¹¹ are independently selected from hydrogen, fluoro, chloro,    methyl and methoxy.

Within the invention, are embodiments where a limited number of R⁸-R¹¹are different from hydrogen, e.g.:

-   only one of R⁸-R¹¹ is different from hydrogen and preferably    selected from the group consisting of hydrogen, fluoro, chloro,    methyl and methoxy, while rest of R⁸-R¹¹ are hydrogen;-   two of R⁸-R¹¹ are different from hydrogen and preferably selected    from the group consisting of hydrogen, fluoro, chloro, methyl and    methoxy while and two of R⁸⁻¹¹ are hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R⁸ is selected from the group consisting of halogen (preferably    fluoro or chloro), methyl and methoxy and R⁷ and R⁹⁻¹¹ are hydrogen;-   R⁹ is selected from the group consisting of halogen (preferably    fluoro or chloro), methyl and methoxy and R⁷, R⁸ and R¹⁰⁻¹¹ are    hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof: only oneof R⁸⁻¹¹ is different from hydrogen and is selected from the groupconsisting of halogen (e.g. fluoro or chloro), methyl, methoxy, hydroxyand cyano.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R⁸ is hydroxy; R⁸ is methoxy; R⁸ is methyl; R⁸ is cyano; R⁸ is    chloro; R⁸ is fluoro; in a preferred embodiment, the rest of R⁸ to    R¹¹ are hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R⁹ is fluoro; R⁹ is chloro; R⁹ is bromo; R⁹ is iodo; R⁹ is methoxy;    R⁹ is methyl; R⁹ is hydroxy; in a preferred embodiment, the rest of    R⁸ to R¹¹ are hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R¹⁰ is fluoro; R¹⁰ is chloro; R¹⁰ is bromo; R¹⁰ is methyl; R¹⁰ is    cyano; R¹⁰ is CF₃; R¹⁰ is methoxy; in a preferred embodiment, the    rest of R⁸ to R¹¹ are hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof:

-   R¹¹ is methyl; R¹¹ is ethyl; R¹¹ is methoxy; R¹¹ is chloro; R¹¹ is    fluoro; in a preferred embodiment, the rest of R⁸ to R¹¹ are    hydrogen.

To further illustrate the invention, without limitation, the followingembodiments of formula IA are within the scope of the invention, inparticular for the compounds as the free base or salt thereof: R¹⁰ andR¹¹ are selected independently from the group consisting of hydrogen,methyl, fluoro and chloride.

To further illustrate the invention, without limitation, the followingembodiments of R¹³ are within the scope of the invention, in particularfor the compounds as the free base or salt thereof:

-   R¹³ is hydrogen;-   R¹³ is C₁₋₆-alkyl;-   R¹³ is C₁₋₄-alkyl;-   R¹³ is methyl.

One embodiment, relates to compounds of formula IA, wherein R¹³ ishydrogen or a C₁₋₆-alkyl, e.g. a C₁₋₄-alkyl, such as methyl and whereR¹-R¹¹ are as defined herein.

To further illustrate the invention, without limitation, the followingembodiment are within the scope of the invention, in particular for thecompounds as the free base or salt thereof: the compound has the formulaIA where R¹ is hydrogen, R² is hydrogen or C₁₋₆-alkyl, preferablyC₁₋₄-alkyl, such as methyl, R³-R⁶ are independently selected fromhydrogen, methyl and halogen, e.g. chloro or fluoro, R⁷ is hydrogen ormethyl, R⁸⁻¹¹ are independently selected from hydrogen, methyl, methoxyand halogen, e.g. chloro or fluoro, and R¹³ is hydrogen, and where atmost one or two of R⁸-R¹¹ are different from hydrogen and at most one ortwo of R³-R⁶ are different from hydrogen.

In a further embodiment, the compound according to the invention isselected from the following list:

Compound no. Compound name 1 [2-(1H-Indol-3-ylsulfanyl)benzyl] dimethylamine 2 [2-(5-cyano-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 3[2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 4[2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 5[2-(5-Fluoro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 6[2-(5-Chloro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 7Dimethyl-[2-(7-methyl-1H-indol-3-ylsulfanyl)benzyl]-amine 8[2-(7-Methoxy-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 9[2-(5-Methoxy-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 10[2-(6-Fluoro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 11[2-(6-Chloro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 12Dimethyl-[2-(2-methyl-1H-indol-3-ylsulfanyl)benzyl]-amine 13Dimethyl-[2-(6-methyl-1H-indol-3-ylsulfanyl)benzyl]-amine 14[2-(4-cyano-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 15Dimethyl-[2-(1-methyl-1H-indol-3-ylsulfanyl)benzyl] amine 16Dimethyl-[2-(4-methyl-1H-indol-3-ylsulfanyl)benzyl] amine 17[2-(4-Hydroxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 18[2-(6-cyano-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 19[2-(7-Chloro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 20[2-(6-Methoxy-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 21[2-(4-Methoxy-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine 22[2-(1H-Indol-3-ylsulfanyl)benzyl]methyl amine 23[2-(6-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine 24[2-(5-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine 25Methyl-[2-(4-methyl-1H-indol-3-ylsulfanyl)benzyl] amine 26[2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine 27Methyl-[2-(2-methyl-1H-indol-3-ylsulfanyl)benzyl] amine 28[2-(5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 29Methyl-[2-(5-methyl-1H-indol-3-ylsulfanyl)benzyl] amine 30Methyl-[2-(7-methyl-1H-indol-3-ylsulfanyl)benzyl] amine 31[2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine 32[2-(7-Ethyl-1H-indol-3-ylsulfanyl)benzyl]methyl amine 33[2-(6-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine 34[2-(5-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine 35[2-(6-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine 36[2-(5-Methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 37[2-(5,6-Dimethoxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 38[2-(6-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 39Methyl-[2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl] amine 40[2-(4,7-Dimethoxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 41[2-(5-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine 42[2-(4-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine 43[2-(5-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 44[2-(7-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine 45[5-Chloro-2-(1H-indol-3-ylsulfanyl)-benzyl]methyl amine 46Methyl-[2-(6-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzyl] amine 47[2-(5-Hydroxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 48[2-(4-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 49[2-(7-Chloro-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 50[2-(5-Iodo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 51[2-(6-Cyano-1H-indol-3-ylsulfanyl)-benzyl]methyl amine 52[2-(1H-Indol-3-ylsulfanyl)-5-methyl-benzyl]methyl amine 53Methyl-[2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl] amine 54[2-(5,6-Dimethoxy-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine55 [5-Fluoro-2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]-methyl-amine 56[5-Fluoro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 57[2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine 58[2-(7-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine 59[5-Fluoro-2-(6-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine60 [5-Fluoro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 61[2-(4-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine 623-(4-Fluoro-2-methylaminomethyl-phenylsulfanyl)-2-methyl-1H-indol-4-ol63 3-(4-Fluoro-2-methylaminomethyl-phenylsulfanyl)-1H-indol-6-ol 64[5-Fluoro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 65[5-Fluoro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 66[2-(6-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine 67[2-(5-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine 68[5-Fluoro-2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 69[5-Fluoro-2-(5-methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine70 [2-(5-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine 71[5-Fluoro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 72[2-(6-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine 73[5-Fluoro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 74[5-Fluoro-2-(6-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 75[5-Fluoro-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 76[5-Fluoro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 77[5-Fluoro-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 78[5-Fluoro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 79[5-Fluoro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 80[5-Fluoro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine81 [5-Chloro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 82[5-Chloro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 83[5-Chloro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 84[5-Chloro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 85[5-Chloro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 86[5-Chloro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 87[5-Chloro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 88[5-Chloro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine89[2-(5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine90 Methyl-[5-methyl-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-amine 91[2-(7-Ethyl-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 92[2-(6-Methoxy-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 93Methyl-[5-methyl-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-amine 94[2-(4-Methoxy-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 95[2-(6-Bromo-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 96[2-(6-Fluoro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 97[2-(4-Fluoro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 983-(4-Methyl-2-methylaminomethyl-phenylsulfanyl)-1H-indol-6-ol 99[5-Chloro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 100[2-(6-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 101[2-(5-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 1025-Fluoro-3-(2-piperidin-1-ylmethyl-phenylsulfanyl)-1H-indole 1035-Fluoro-3-(2-morpholin-4-ylmethyl-phenylsulfanyl)-1H-indole 1045-Fluoro-3-(2-pyrrolidin-1-ylmethyl-phenylsulfanyl)-1H-indole 105[4-Chloro-2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 106[4-Chloro-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 107[4-Chloro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 108[4-Chloro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 109[4-Chloro-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 110[4-Chloro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 111[4-Chloro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 112[4-Chloro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 113[4-Chloro-2-(7-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 114[4-Chloro-2-(7-ethyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 115[4-Chloro-2-(5-methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine116 [4-Chloro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine117 [4-Chloro-2-(6-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine118 [4-Chloro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine119 [4-Chloro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine120 [4-Chloro-2-(5-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine121 [4-Chloro-2-(6-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine122 [4-Chloro-2-(4-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine123 [4-Chloro-2-(7-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine124 [4-Chloro-2-(1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 125[4-Chloro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 126[4-Chloro-2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]-methyl-amine 127[4-Chloro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine128 2-(5-Fluoro-1H-indol-3-ylsulfanyl)-benzylamine 129[2-(5-Fluoro-4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 130[2-(4,5-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 131[2-(4,6-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 1323-(2-Methylaminomethyl-phenylsulfanyl)-1H-indol-4-ol 1332-(6-Fluoro-1H-indol-3-ylsulfanyl)-benzylamine 134[2-(5,6-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine 1356-Fluoro-3-(2-methylaminomethyl-phenylsulfanyl)-1H-indol-5-ol 136[2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine 137[2-(1H-Indol-5-ylsulfanyl)-benzyl]-methyl-amine 138[2-(1H-Indol-4-ylsulfanyl)-benzyl]-methyl-amine 139[2-(1H-Indol-6-ylsulfanyl)-benzyl]-methyl-amine 140[2-(1H-Indol-7-ylsulfanyl)-benzyl]-methyl-amineas the free base or a salt thereof, such as a pharmaceuticallyacceptable salt.

An non limiting aspect of the invention concerns such compoundsaccording to the below embodiments 1-87:

-   -   1. A compound represented by the general formulas IA to IF:

-   -    Wherein        -   R¹-R² are independently selected from hydrogen,            C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, and            C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or R¹ and R² together            with the nitrogen form a 4-7 membered ring containing zero            or one double bond, optionally said ring in addition to said            nitrogen comprises one further heteroatom selected from            nitrogen, oxygen and sulphur;        -   R³-R¹² are independently selected from hydrogen, halogen,            cyano, nitro, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,            C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,            C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,            C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,            C₁₋₆-alk(en/yn)ylaminocarbonyl,            di-(C₁₋₆-alk(en)yl)aminocarbonyl, hydroxy,            C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk(en/yn)ylthio,            halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)ylsulfonyl,            halo-C₁₋₆-alk(en/yn)ylsulfanyl, and            C₁₋₆-alk(en/yn)ylsulfonyl; and        -   R¹³ is selected from hydrogen, C₁₋₆-alk(en/yn)yl,            C₃₋₈-cycloalk(en)yl, and            C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;    -    or a salt thereof.    -   2. The compound of embodiment 1, wherein R¹-R² are independently        selected from hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,        and C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or a salt thereof.    -   3. The compound of embodiment 1, wherein R¹-R² are independently        selected from hydrogen and C₁₋₆-alkyl; or a salt thereof.    -   4. The compound of embodiment 1, wherein R¹ is hydrogen and R²        is methyl; or a salt thereof.    -   5. The compound of embodiment 1, wherein R¹ and R² are methyl;        or a salt thereof.    -   6. The compound of embodiment 1, wherein R¹ and R² are hydrogen;        or a salt thereof.    -   7. The compound of embodiment 1, wherein R¹ and R² together with        the nitrogen form a 4-7 membered ring containing zero or one        double bond, optionally said ring in addition to said nitrogen        comprises one further heteroatom selected from nitrogen, oxygen        and sulphur; or a salt thereof.    -   8. The compound of embodiment 1, wherein R¹ and R² together with        the nitrogen form a ring selected from the group consisting of        azetidine, pyrrolidine, piperidine, piperazine, homopiperazine        or morpholine; or a salt thereof.    -   9. The compound of any of embodiments 1-8, wherein R³-R¹² are        independently selected from hydrogen, halogen, cyano,        C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,        C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,        aminocarbonyl, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkylamino)carbonyl, hydroxy, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkylsulfonyl,        halo-C₁₋₆-alkylsulfanyl, and C₁₋₆-alkylsulfonyl; or a salt        thereof.    -   10. The compound of any of embodiments 1-8, wherein R³-R⁶ are        independently selected from hydrogen, halogen, cyano, nitro,        C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,        C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,        C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,        C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,        C₁₋₆-alk(en/yn)ylaminocarbonyl,        di-(C₁₋₆-alk(en)yl)aminocarbonyl, hydroxy, C₁₋₆-alk(en/yn)yloxy,        C₁₋₆-alk(en/yn)ylthio, halo-C₁₋₆-alk(en/yn)yl,        halo-C₁₋₆-alk(en/yn)ylsulfonyl, halo-C₁₋₆-alk(en/yn)ylsulfanyl,        and C₁₋₆-alk(en/yn)ylsulfonyl; or a salt thereof.    -   11. The compound of any of embodiments 1-8, wherein R³-R⁶ are        independently selected from hydrogen, halogen, cyano,        C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,        C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,        aminocarbonyl, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkylamino)carbonyl, hydroxy, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkylsulfonyl,        halo-C₁₋₆-alkylsulfanyl, and C₁₋₆-alkylsulfonyl; or a salt        thereof.    -   12. The compound of any of embodiments 1-8, wherein R³-R⁶ are        independently selected from hydrogen, halogen, C₁₋₆-alkyloxy and        C₁₋₆-alkyl; or a salt thereof.    -   13. The compound of any of embodiments 1-8, wherein R³-R⁶ are        independently selected from hydrogen, halogen, methoxy and        methyl; or a salt thereof.    -   14. The compound of any of embodiments 1-13, wherein only one or        two of R³-R⁶ is different from hydrogen.    -   15. The compound of any of embodiments 1-13, wherein only one of        R³-R⁶ is different from hydrogen; or a salt thereof.    -   16. The compound of any of embodiments 1-9, wherein three of        R³-R⁶ are hydrogen and one of R³-R⁶ is halogen; or a salt        thereof.    -   17. The compound of any of embodiments 1-9, wherein three of        R³-R⁶ are hydrogen and one of R³-R⁶ is methyl; or a salt        thereof.    -   18. The compound of any of embodiments 15-17, wherein R⁴ is        different from hydrogen; or a salt thereof.    -   19. The compound of any of embodiments 15-17, wherein R⁵ is        different from hydrogen; or a salt thereof.    -   20. The compound of any of embodiments 1-9, wherein R³-R⁶ are        hydrogen; or a salt thereof.    -   21. The compound of any of embodiments 1-20, wherein R¹³ is        hydrogen; or a salt thereof.    -   22. The compound of any of embodiments 1-20, wherein R¹³ is        C₁₋₆-alkyl; or a salt thereof    -   23. The compound of any of embodiments 1-20, wherein R¹³ is        methyl; or a salt thereof.    -   24. The compound of any of embodiments 1-23, wherein the        compound has the formula IA; or a salt thereof.    -   25. The compound of any of embodiments 1-23, wherein the        compound has the formula IB; or a salt thereof.    -   26. The compound of any of embodiments 1-23, wherein the        compound has the formula IC; or a salt thereof.    -   27. The compound of any of embodiments 1-23, wherein the        compound has the formula ID; or a salt thereof.    -   28. The compound of any of embodiments 1-23, wherein the        compound has the formula IE; or a salt thereof.    -   29. The compound of any of embodiments 1-23, wherein the        compound has the formula IF, or a salt thereof.    -   30. The compound of any of embodiments 1-23, wherein the        compound has the formula IA and R⁷ is selected from the group        consisting of hydrogen, halogen, cyano, nitro,        C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,        C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,        C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,        C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,        C₁₋₆-alk(en/yn)ylaminocarbonyl,        di-(C₁₋₆-alk(en)yl)aminocarbonyl, hydroxy, C₁₋₆-alk(en/yn)yloxy,        C₁₋₆-alk(en/yn)ylthio, halo-C₁₋₆-alk(en/yn)yl,        halo-C₁₋₆-alk(en/yn)ylsulfonyl, halo-C₁₋₆-alk(en/yn)ylsulfanyl,        and C₁₋₆-alk(en/yn)ylsulfonyl; or a salt thereof.    -   31. The compound of any of embodiments 1-23, wherein the        compound has the formula IA and R⁷ is selected from the group        consisting of hydrogen, halogen, cyano, C₁₋₆-alkyl,        C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,        C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,        aminocarbonyl, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkylamino)carbonyl, hydroxy, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkylsulfonyl,        halo-C₆-alkylsulfanyl, and C₁₋₆-alkylsulfonyl; or a salt        thereof.    -   32. The compound of any of embodiments 1-23, wherein the        compound has the formula IA and R⁷ is hydrogen; or a salt        thereof.    -   33. The compound of any of embodiments 1-23, wherein the        compound has the formula IA and R⁷ is methyl; or a salt thereof.    -   34. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸-R¹¹ are independently selected from hydrogen, halogen, cyano,        nitro, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,        C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,        C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,        C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,        C₁₋₆-alk(en/yn)ylaminocarbonyl,        di-(C₁₋₆-alk(en)yl)aminocarbonyl, hydroxy, C₁₋₆-alk(en/yn)yloxy,        C₁₋₆-alk(en/yn)ylthio, halo-C₁₋₆-alk(en/yn)yl,        halo-C₁₋₆-alk(en/yn)ylsulfonyl, halo-C₁₋₆-alk(en/yn)ylsulfanyl,        and C₁₋₆-alk(en/yn)ylsulfonyl; or a salt thereof.    -   35. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸-R¹¹ are independently selected from hydrogen, halogen, cyano,        C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,        C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,        aminocarbonyl, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkylamino)carbonyl, hydroxy, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkylsulfonyl,        halo-C₁₋₆-alkylsulfanyl, and C₁₋₆-alkylsulfonyl; or a salt        thereof.    -   36. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸-R¹¹ are independently selected from hydrogen, halogen, cyano,        methyl, hydroxy, methoxy and trifluoromethyl; or a salt thereof.    -   37. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸-R¹¹ are independently selected from hydrogen, halogen, methyl        and methoxy; or a salt thereof.    -   38. The compound of any of embodiments 34-36, wherein only one        of R⁸-R¹¹ is different from hydrogen while rest of R⁸-R¹¹ are        hydrogen; or a salt thereof.    -   39. The compound of any of embodiments 34-36, wherein the        compound has the formula IA and two of R⁸⁻¹¹ are different from        hydrogen and two of R⁸⁻¹¹ are hydrogen; or a salt thereof.    -   40. The compound of any one of embodiments 1-23 or 30-37,        wherein the compound has the formula IA and R⁸ is selected from        the group consisting of halogen, methyl, and methoxy; or a salt        thereof.    -   41. The compound of embodiments 40, wherein R⁹⁻¹¹ are hydrogen;        or a salt thereof.    -   42. The compound of embodiments 41, wherein R⁷ is hydrogen; or a        salt thereof.    -   43. The compound of any one of embodiments 1-23 or 30-37,        wherein the compound has the formula IA and R⁹ is selected from        the group consisting of halogen, methyl, and methoxy; or a salt        thereof.    -   44. The compound of embodiments 43, wherein R⁸ and R¹⁰⁻¹¹ are        hydrogen; or a salt thereof.    -   45. The compound of embodiments 44, wherein R⁷ is hydrogen; or a        salt thereof.    -   46. The compound of any of embodiments 1-23 or 30-33, wherein        the compound has the formula IA and wherein R⁸⁻¹¹ are hydrogen;        or a salt thereof.    -   47. The compound of embodiments 38 or 39, wherein substituent(s)        of R⁸⁻¹¹ being different from hydrogen is/are selected from the        group consisting of halogen, methyl, methoxy, hydroxy, cyano; or        a salt thereof.    -   48. The compound of embodiment 1, wherein the compound has the        formula IA, and        -   R¹ is hydrogen and R² is hydrogen or a C₁₋₆-alkyl;        -   R³-R⁶ are independently selected from hydrogen, halogen and            methyl, wherein at most one or two of R³-R⁶ are different            from hydrogen;        -   R⁷ is hydrogen or methyl        -   R⁸⁻¹¹ are independently selected from hydrogen, halogen,            methyl, and methoxy wherein at most one or two of R⁸-R¹¹ are            different from hydrogen;        -   R¹³ is hydrogen.        -   or a salt thereof.    -   49. The compound of embodiment 1 wherein the compound has the        formula IA,        -   R¹ is hydrogen and R² is methyl;        -   R³-R⁶ are as defined in any one of claims 13-20;        -   R⁷ is hydrogen        -   R⁸-R¹¹ are as defined in claim 36-47        -   R¹³ is hydrogen;        -   or a salt thereof.    -   50. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸ is hydroxy; or a salt thereof.    -   51. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸ is methoxy; or a salt thereof.    -   52. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸ is methyl; or a salt thereof.    -   53. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸ is cyano; or a salt thereof.    -   54. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸ is Cl; or a salt thereof.    -   55. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁸ is F; or a salt thereof.    -   56. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is cyano; or a salt thereof.    -   57. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is F; or a salt thereof.    -   58. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is Cl; or a salt thereof.    -   59. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is Br; or a salt thereof.    -   60. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is I; or a salt thereof.    -   61. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is methoxy; or a salt thereof.    -   62. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is methyl; or a salt thereof.    -   63. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R⁹ is hydroxy; or a salt thereof.    -   64. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ is F; or a salt thereof.    -   65. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ is Cl; or a salt thereof.    -   66. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ is Br; or a salt thereof.    -   67. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ is methyl; or a salt thereof.    -   68. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ is cyano; or a salt thereof.    -   69. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ is CF₃; or a salt thereof.    -   70. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ is methoxy; or a salt thereof.    -   71. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹¹ is methyl; or a salt thereof.    -   72. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹¹ is ethyl; or a salt thereof.    -   73. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹¹ is methoxy; or a salt thereof.    -   74. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹¹ is Cl; or a salt thereof.    -   75. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹¹ is F; or a salt thereof.    -   76. The compound of any of embodiments 50-75, wherein the rest        of R⁸ to R¹¹ are hydrogen; or a salt thereof.    -   77. The compound of any of embodiments 1-23 or any of        embodiments 30-33, wherein the compound has the formula IA and        R¹⁰ and R¹¹ are selected independently from the group consisting        of hydrogen, methyl, fluoro and chloride; or a salt thereof.    -   78. The compound of embodiment 77, wherein at least one of R¹⁰        and R¹¹ is hydrogen; or a salt thereof.    -   79. The compound of claim 1 selected from the group consisting        of:        -   [2-(1H-Indol-3-ylsulfanyl)benzyl]dimethyl amine;        -   [2-(5-cyano-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(5-Fluoro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(5-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   Dimethyl-[2-(7-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   [2-(7-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(5-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(6-Fluoro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(6-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   Dimethyl-[2-(2-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   Dimethyl-[2-(6-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   [2-(4-cyano-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   Dimethyl-[2-(1-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   Dimethyl-[2-(4-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   Dimethyl-[2-(4-hydroxy-1H-indol-3-ylsulfanyl)benzyl]amine        -   [2-(6-cyano-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(7-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(6-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(4-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine        -   [2-(1H-Indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(6-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(5-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   Methyl-[2-(4-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   [2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   Methyl-[2-(2-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   [2-(5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]methyl            amine        -   Methyl-[2-(5-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   Methyl-[2-(7-methyl-1H-indol-3-ylsulfanyl)benzyl]amine        -   [2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(7-Ethyl-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(6-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(5-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(6-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(5-Methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]methyl            amine        -   [2-(5,6-Dimethoxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine        -   [2-(6-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine        -   Methyl-[2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]amine        -   [2-(4,7-Dimethoxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine        -   [2-(5-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(4-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [2-(5-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine        -   [2-(7-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine        -   [5-Chloro-2-(1H-indol-3-ylsulfanyl)-benzyl]methyl amine        -   Methyl-[2-(6-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzyl]amine;        -   [5-Hydroxy-2-(1H-indol-3-ylsulfanyl)-benzyl]methyl amine;        -   [2-(4-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine;        -   [2-(7-Chloro-1H-indol-3-ylsulfanyl)-benzyl]methyl amine;        -   [2-(5-Iodo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine;        -   [2-(6-Cyano-1H-indol-3-ylsulfanyl)-benzyl]methyl amine;        -   [2-(1H-Indol-3-ylsulfanyl)-5-methyl-benzyl]methyl amine;        -   [2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]methyl amine;        -   [2-(5,6-Dimethoxy-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   [5-Fluoro-2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   [2-(7-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   [5-Fluoro-2-(6-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(4-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   3-(4-Fluoro-2-methylaminomethyl-phenylsulfanyl)-2-methyl-1H-indol-4-ol;        -   3-(4-Fluoro-2-methylaminomethyl-phenylsulfanyl)-1H-indol-6-ol;        -   [5-Fluoro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(6-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   [2-(5-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   [5-Fluoro-2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(5-methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(5-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   [5-Fluoro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(6-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;        -   [5-Fluoro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(6-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Fluoro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [5-Chloro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   Methyl-[5-methyl-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-amine;        -   [2-(7-Ethyl-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   [2-(6-Methoxy-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   Methyl-[5-methyl-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-amine;        -   [2-(4-Methoxy-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   [2-(6-Bromo-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   [2-(6-Fluoro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   [2-(4-Fluoro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   3-(4-Methyl-2-methylaminomethyl-phenylsulfanyl)-1H-indol-6-ol;        -   [5-Chloro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(6-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   [2-(5-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   5-Fluoro-3-(2-piperidin-1-ylmethyl-phenylsulfanyl)-1H-indole;        -   5-Fluoro-3-(2-morpholin-4-ylmethyl-phenylsulfanyl)-1H-indole;        -   5-Fluoro-3-(2-pyrrolidin-1-ylmethyl-phenylsulfanyl)-1H-indole;        -   [4-Chloro-2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(7-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(7-ethyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(5-methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(6-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(5-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(6-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(4-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(7-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]-methyl-amine;        -   [4-Chloro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   2-(5-Fluoro-1H-indol-3-ylsulfanyl)-benzylamine;        -   [2-(5-Fluoro-4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(4,5-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(4,6-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   3-(2-Methylaminomethyl-phenylsulfanyl)-1H-indol-4-ol;        -   2-(6-Fluoro-1H-indol-3-ylsulfanyl)-benzylamine;        -   [2-(5,6-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;        -   6-Fluoro-3-(2-methylaminomethyl-phenylsulfanyl)-1H-indol-5-ol;        -   [2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;        -   [2-(1H-Indol-5-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(1H-Indol-4-ylsulfanyl)-benzyl]-methyl-amine;        -   [2-(1H-Indol-6-ylsulfanyl)-benzyl]-methyl-amine; and        -   [2-(1H-Indol-7-ylsulfanyl)-benzyl]-methyl-amine;        -   or a salt thereof.    -   80. The compound of any of embodiments 1-23, wherein the        compound has the formula IB and R¹² is hydrogen or methyl; or a        salt thereof.    -   81. A compound of any one of embodiments 1-80 or a        pharmaceutically acceptable salt thereof for use in a        medicament.    -   82. The use of a compound of any one of embodiments 1-80 or a        pharmaceutically acceptable salt thereof for the preparation of        a medicament for the treatment of affective disorders.    -   83. The use of a compound of any one of embodiments 1-80 or a        pharmaceutically acceptable salt thereof for the preparation of        a medicament for the treatment of depression, anxiety disorders        including general anxiety disorder, social anxiety disorder,        post traumatic stress disorder, obsessive compulsive disorder,        panic disorder, panic attacks, specific phobias, social phobia        or agoraphobia.    -   84. The use of a compound of any one of embodiments 1-80 or a        pharmaceutically acceptable salt thereof for the preparation of        a medicament for the treatment of depression.    -   85. A method for the treatment of an affective disorder        comprising administering a therapeutically effective amount of a        compound of any one of embodiments 1-80 or a pharmaceutically        acceptable salt thereof.    -   86. A method for the treatment of depression, anxiety disorders        including general anxiety disorder, social anxiety disorder,        post traumatic stress disorder, obsessive compulsive disorder,        panic disorder, panic attacks, specific phobias, social phobia        or agoraphobia comprising administering a therapeutically        effective amount of a compound of any one of embodiments 1-80 or        a pharmaceutically acceptable salt thereof.    -   87. A pharmaceutical composition comprising a compound of any        one of embodiments 1-80 or a pharmaceutically acceptable salt        thereof.

The present invention comprises the free bases of the compounds of theinvention.

The present invention furthermore comprises salts of the compounds ofthe invention, typically, pharmaceutically acceptable salts. Such saltsinclude pharmaceutical acceptable acid addition salts, pharmaceuticallyacceptable metal salts, ammonium and alkylated ammonium salts. Acidaddition salts include salts of inorganic acids as well as organicacids.

Examples of suitable inorganic acids include hydrochloric, hydrobromic,hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.

Examples of suitable organic acids include formic, acetic,trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric,fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic,malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,p-toluenesulfonic acids, theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline and the like.

Also intended as pharmaceutical acceptable acid addition salts are thehydrates, which the present compounds, are able to form.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

The compounds of the present invention may have one or more asymmetriccentres and it is intended that any optical isomers (i.e. enantiomers ordiastereomers), as separated, pure or partially purified optical isomersand any mixtures thereof including racemic mixtures, i.e. a mixture ofstereoisomeres, are included within the scope of the invention Racemicforms can be resolved into the optical antipodes by known methods, forexample, by separation of diastereomeric salts thereof with an opticallyactive acid, and liberating the optically active amine compound bytreatment with a base. Another method for resolving racemates into theoptical antipodes is based upon chromatography on an optically activematrix. Racemic compounds of the present invention can also be resolvedinto their optical antipodes, e.g. by fractional crystallization. Thecompounds of the present invention may also be resolved by the formationof diastereomeric derivatives. Additional methods for the resolution ofoptical isomers, known to those skilled in the art, may be used. Suchmethods include those discussed by J. Jaques, A. Collet and S. Wilen in“Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, New York(1981). Optically active compounds can also be prepared from opticallyactive starting materials.

Furthermore, when a double bond or a fully or partially saturated ringsystem is present in the molecule geometric isomers may be formed. It isintended that any geometric isomers, as separated, pure or partiallypurified geometric isomers or mixtures thereof are included within thescope of the invention. Likewise, molecules having a bond withrestricted rotation may form geometric isomers. These are also intendedto be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming pharmacologically active substances. In general, suchprodrugs will be functional derivatives of the compounds of the generalformula I, IA, IB, IC, IE or IF which are readily convertible in vivointo the required compound of the formula I, IA, IB, IC, IE or IF.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the presentcompounds.

As described above the compounds of the invention,2-(1H-indolylsulfanyl)-benzyl amine derivatives, are serotonin reuptakeinhibitors.

Accordingly, one embodiment of invention relates to compounds of FormulaI, IA, IB, IC, IE or IF (e.g. formula IA) as the free base or a saltthereof, wherein R¹-R¹³ are as described herein, which compounds areserotonin reuptake inhibitors, i.e., e.g., having a binding affinity(IC50) of 5 μM or less, typically of 1 μM or less, preferably less than500 nM or less than 100 nM or less than 50 nM, preferably as measured bythe method described in Example 9—Transporter Binding Assay.

One embodiment of invention relates to compounds of formula I, IA, IB,IC, IE or IF (e.g. formula IA) as the free base or salts thereof,wherein R¹-R¹³ are as described herein, which compounds arenorepinephrine reuptake inhibitors, i.e., e.g., having a bindingaffinity (IC50) of 5 μM or less, typically of 1 μM or less, preferablyless than 500 nM, less than 100 nM or less than 50 nM, preferably asmeasured by the method described in Example 9—Transporter binding assay.

A further embodiment of invention relates to compounds of formula I, IA,IB, IC, IE or IF (e.g. formula (IA)) as the free base or salts thereof,wherein R¹-R¹³ are as described herein, which compounds are dopaminereuptake inhibitors, i.e., e.g., having a binding affinity (IC50) of 5μM or less, typically of 1 μM or less, preferably less than 500 nM, lessthan 100 nM or less than 50 nM, preferably as measured by the methoddescribed in Example 9-Transporter binding assay.

In particular, the invention provides compounds possessing the combinedeffect of serotonin reuptake inhibition and norepinephrine reuptakeinhibition. Accordingly, a preferred embodiment relates to compounds ofthe invention (i.e. the compounds of formula I, IA, IB, IC, IE or IF(e.g. of formula IA) for which R¹-R¹³ are as described herein) beingdual serotonin and norepinephrine reuptake inhibitors, i.e. compounds ofthe invention which are both norepinephrine reuptake inhibitors andserotonin reuptake inhibitors, each of which are as defined above.

In one embodiment, it is preferred for the compounds of the inventionpossessing the combined effect of serotonin reuptake inhibition andnorepinephrine reuptake inhibition as described above, that suchcompounds are not also dopamine reuptake inhibitors. Thus, thisembodiment relates to compounds of the invention having a bindingaffinity for the serotonin transporter which is at least 5, preferablyat least 10 or even more preferred at least 20 or 30 times higher thanthe binding affinity for the dopamine transporter, preferably asmeasured by the methods described in Example 9—Transporter bindingassay.

In a further aspect the invention provides compounds possessing thecombined effect of serotonin reuptake inhibition, norepinephrine anddopamine reuptake inhibition.

Accordingly, a preferred embodiment relates to compounds of theinvention (i.e. the compounds of formula I, IA, IB, IC, IE or IF (e.g.formula IA) for which R¹-R¹³ are as described herein) being tripleserotonin, norepinephrine and dopamine reuptake inhibitors, i.e.compounds of the invention which are at the same time norepinephrinereuptake inhibitors, serotonin reuptake inhibitors, and dopaminereuptake inhibitors, each of which are as defined above.

Pharmaceutical Use

In a further aspect the invention provides a compound of formula I, IA,IB, IC, ID, IE or IF for use as a medicament.

As mentioned above the compounds of the invention are inhibitors of theserotonin transporter. In particular is provided compounds of theinvention which are dual inhibitors of the serotonin and noradrenalinetransporters. The compounds of the invention may thus be useful fortreatment in a disorder or disease wherein the serotonin and/ornoradrenaline are implicated.

Accordingly, in a further aspect the invention relates to a compound ofthe invention as the free base or a salt thereof for use as amedicament, i.e. in particular a compound represented by the generalformula I, IA, IB, IC, IE or IF, e.g. formula IA, wherein

-   -   R¹-R² are independently selected from hydrogen,        C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, and        C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or R¹ and R² together        with the nitrogen form a 4-7 membered ring containing zero or        one double bond, optionally said ring in addition to said        nitrogen comprises one further heteroatom selected from        nitrogen, oxygen and sulphur; which ring structure is        substituted or unsubstituted as described herein;    -   R³-R¹² are independently selected from hydrogen, halogen, cyano,        nitro, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,        C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino,        C₁₋₆-alk(en/yn)ylamino, di-(C₁₋₆-alk(en/yn)yl)amino,        C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,        C₁₋₆-alk(en/yn)ylaminocarbonyl,        di-(C₁₋₆-alk(en)yl)aminocarbonyl, hydroxy, C₁₋₆-alk(en/yn)yloxy,        C₁₋₆-alk(en/yn)ylthio, halo-C₁₋₆-alk(en/yn)yl,        halo-C₁₋₆-alk(en/yn)ylsulfonyl, halo-C₁₋₆-alk(en/yn)ylsulfanyl,        and C₁₋₆-alk(en/yn)ylsulfonyl; and    -   R¹³ is selected from hydrogen, C₁₋₆-alk(en/yn)yl,        C₃₋₈-cycloalk(en)yl, and C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;

as the free base or a salt thereof;

with the provisos that:

-   -   when the sulphur atom is attached via atom nr. 2 of the indole        then R⁷ does not exist;    -   when the sulphur atom is attached via atom nr. 3 of the indole        then R¹² does not exist;    -   when the sulphur atom is attached via atom nr. 4 of the indole        then R⁸ does not exist;    -   when the sulphur atom is attached via atom nr. 5 of the indole        then R⁹ does not exist;    -   when the sulphur atom is attached via atom nr. 6 of the indole        then R¹⁰ does not exist; and    -   when the sulphur atom is attached via atom nr. 7 of the indole        then R¹¹ does not exist.

By the expression a compound of the invention is meant any one of theembodiments of formula I, IA, IB, IC, IE or IF, in particular formula IAdescribed herein.

The present invention also relates to a pharmaceutical compositioncomprising a compound of the invention as the free base or a saltthereof and a pharmaceutically acceptable carrier or diluent.

In an embodiment of the pharmaceutical composition, the compound of theinvention is present in an amount of from about 0.001 to about 100 mg/kgbody weight per day.

The present invention also relates to use of a compound of the inventionas the free base or a salt thereof for the preparation of apharmaceutical composition for the treatment of a disease or disorder,wherein a serotonin reuptake inhibitor is beneficial. The medicament maycomprise any one of the embodiments of formula I, IA, IB, IC, IE or IFdescribed herein.

The present invention also relates to use of a compound of the inventionas the free base or a salt thereof for the preparation of apharmaceutical composition for the treatment of a disease or disorder,wherein the combined effect of serotonin reuptake inhibition andnorepinephrine reuptake inhibition is beneficial. The medicament maycomprise any one of the embodiments of formula I, IA, IB, IC, IE or IFdescribed herein.

The present invention also relates to use of a compound of the inventionas the free base or a salt thereof for the preparation of apharmaceutical composition for the treatment of a disease or disorder,the combined effect of serotonin reuptake inhibition and norepinephrineand dopamine reuptake inhibition is beneficial. The medicament maycomprise any one of the embodiments of formula I, IA, IB, IC, IE or IFdescribed herein.

A further embodiment of the invention relates to the use of a compoundof formula I, IA, IB, IC, ID, IE or IF for the preparation of apharmaceutical composition for the treatment of affective disorders,pain disorders, ADHD and stress urinary incontinence.

In particular the invention also relates to use of a compound of theinvention as the free base or a salt thereof for the preparation of apharmaceutical composition for the treatment of affective disorders. Tofurther illustrate without limiting the invention, the affectivedisorder to be treated is selected from the group consisting ofdepressive disorders and anxiety disorders.

A further embodiment concerns the use of a compound of formula I, IA,IB, IC, ID, IE or IF for the preparation of a pharmaceutical compositionfor the treatment of depressive disorders. Typically, the depressivedisorder to be treated is selected from the group consisting of majordepressive disorder, postnatal depression, dysthymia and depressionassociated with bipolar disorder, alzheimers, psychosis or parkinsons.To further illustrate without limiting the invention, an embodiment ofthe invention concerns the treatment of major depressive disorder;another embodiment concerns the treatment of postnatal depression;another embodiment concerns the treatment of dysthymia; anotherembodiment concerns the treatment of depression associated with bipolardisorder, alzheimers, psychosis or parkinsons. To further illustratewithout limiting the invention, an embodiment of the invention concernsthe treatment of depression associated with bipolar disorder; anotherembodiment concerns the treatment of depression associated withalzheimers; another embodiment concerns the treatment of depressionassociated with psychosis; another embodiment concerns the treatment ofdepression associated with parkinsons.

In a further embodiment the invention also relates to use of a compoundof the invention as the free base or a salt thereof for the preparationof a pharmaceutical composition for the treatment of depression.

In a further embodiment the invention also relates to use of a compoundof the invention as the free base or a salt thereof for the preparationof a pharmaceutical composition for the treatment of anxiety disorders.Typically, the anxiety disorders to be treated are selected from thegroup consisting of general anxiety disorder, social anxiety disorder,post traumatic stress disorder, obsessive compulsive disorder, panicdisorder, panic attacks, specific phobias, social phobia andagoraphobia. In a further embodiment the invention also relates to useof a compound of the invention as the free base or a salt thereof forthe preparation of a pharmaceutical composition for the treatment ofgeneral anxiety disorder. In a further embodiment the invention alsorelates to use of a compound of the invention as the free base or a saltthereof for the preparation of a pharmaceutical composition for thetreatment of social anxiety disorder. In a further embodiment theinvention also relates to use of a compound of the invention as the freebase or a salt thereof for the preparation of a pharmaceuticalcomposition for the treatment of post traumatic stress disorder. In afurther embodiment the present invention also relates to use of acompound of the invention as the free base or a salt thereof thepreparation of a pharmaceutical composition for the treatment ofobsessive compulsive disorder. In a further embodiment the inventionalso relates to use of a compound of the invention as the free base or asalt thereof for the preparation of a pharmaceutical composition for thetreatment of panic disorder. In a further embodiment present inventionalso relates to use of a compound of the invention as the free base or asalt thereof for the preparation of a pharmaceutical composition for thetreatment of panic attacks. In a further embodiment the invention alsorelates to use of a compound of the invention as the free base or a saltthereof for the preparation of a pharmaceutical composition for thetreatment of specific phobias. In a further embodiment the inventionalso relates to use of a compound of the invention as the free base or asalt thereof for the preparation of a pharmaceutical composition for thetreatment of social phobia. In a further embodiment the invention alsorelates to use of a compound of the invention as the free base or a saltthereof for the preparation of a pharmaceutical composition for thetreatment of agoraphobia.

A further aspect of the invention relates to a method for the treatmentof a disease or disorder selected from the group consisting of anaffective disorder, such as depression, anxiety disorders includinggeneral anxiety disorder, social anxiety disorder, post traumatic stressdisorder, obsessive compulsive disorder, panic disorder, panic attacks,specific phobias, social phobia and agoraphobia in a living animal body,including a human, comprising administering to a subject in need thereofa therapeutically effective amount of a compound of the invention as thefree base or a salt thereof, i.e. in particular a compound representedby the general formula I, IA, IB, IC, IE or IF, e.g. formula IA.

In a further embodiment the present invention relates to the use of acompound of formula I, IA, IB, IC, ID or IE as the free base or a saltthereof for the preparation of a pharmaceutical composition for thetreatment of pain disorders. To further illustrate without limiting theinvention, the pain disorder to be treated is selected from the groupconsisting of fibromyalgia syndrome (FMS), overall pain, back pain,shoulder pain, headache as well as pain while awake and during dailyactivities. To further illustrate without limiting the invention, anembodiment of the invention concerns the treatment of fibromyalgiasyndrome; another embodiment concerns the treatment of overall pain;another embodiment concerns the treatment of back pain; anotherembodiment concerns the treatment of shoulder pain; another embodimentconcerns the treatment of headache; another embodiment concerns thetreatment of pain while awake and during daily activities.

In a further embodiment the present invention relates to the use of acompound of formula I, IA, IB, IC, ID or IE as the free base or a saltthereof for the preparation of a pharmaceutical composition for thetreatment of attention deficit hyperactivity disorder.

In a further embodiment the present invention relates to the use of acompound of formula I, IA, IB, IC, ID or IE as the free base or a saltthereof for the preparation of a pharmaceutical composition for thetreatment of stress urinary incontinence.

Pharmaceutical Composition

The compounds of the invention as the free base or the salt thereof maybe administered alone or in combination with pharmaceutically acceptablecarriers or excipients, in either single or multiple doses. Thepharmaceutical compositions according to the invention may be formulatedwith pharmaceutically acceptable carriers or diluents as well as anyother known adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co.,Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, they can be prepared with coatings such asenteric coatings or they can be formulated so as to provide controlledrelease of the active ingredient such as sustained or prolonged releaseaccording to methods well known in the art.

Liquid dosage forms for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Depotinjectable formulations are also contemplated as being within the scopeof the present invention.

Other suitable administration forms include suppositories, sprays,ointments, cremes, gels, inhalants, dermal patches, implants, etc.

In an embodiment of the pharmaceutical composition, the compound of theinvention administered in an amount of from about 0.001 to about 100mg/kg body weight per day.

Conveniently, the compounds of the invention are administered in a unitdosage form containing said compounds in an amount of about 0.01 to 100mg. The total daily dose is usually in the range of about 0.05-500 mg.

A typical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, administered in one or more dosages such as 1 to 3dosages. The exact dosage will depend upon the frequency and mode ofadministration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain from 0.01 to about 1000 mg, preferably from about0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200mg.

For parenteral routes such as intravenous, intrathecal, intramuscularand similar administration, typically doses are in the order of abouthalf the dose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a salt such as a pharmaceutically acceptable saltthereof. One example is an acid addition salt of a compound having theutility of a free base. When a compound of the invention contains a freebase such salts are prepared in a conventional manner by treating asolution or suspension of a free base of the invention with a chemicalequivalent of an acid such as a pharmaceutically acceptable acid.Representative examples are mentioned above.

For parenteral administration, solutions of the compound of theinvention in sterile aqueous solution, aqueous propylene glycol, aqueousvitamin E or sesame or peanut oil may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theaqueous solutions are particularly suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. Thesterile aqueous media employed are all readily available by standardtechniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Examplesof solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc,gelatine, agar, pectin, acacia, magnesium stearate, stearic acid andlower alkyl ethers of cellulose. Examples of liquid carriers are syrup,peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines,polyoxyethylene and water. Similarly, the carrier or diluent may includeany sustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax. Thepharmaceutical compositions formed by combining the compound of theinvention and the pharmaceutical acceptable carriers are then readilyadministered in a variety of dosage forms suitable for the disclosedroutes of administration. The formulations may conveniently be presentedin unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined. amount of the active ingredient, and whichmay include a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation maybe tablette, e.g. placed in a hard gelatine capsule in powder or pelletform or e.g. in the form of a troche or lozenge. The amount of solidcarrier may vary but will usually be from about 25 mg to about 1 g.

If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art.

For example: Tablets may be prepared by mixing the active ingredientwith ordinary adjuvants and/or diluents and subsequently compressing themixture in a conventional tabletting machine. Examples of adjuvants ordiluents comprise: Corn starch, potato starch, talcum, magnesiumstearate, gelatine, lactose, gums, and the like. Any other adjuvants oradditives usually used for such purposes such as colourings,flavourings, preservatives etc. may be used provided that they arecompatible with the active ingredients.

Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to thedesired volume, sterilising the solution and filling it in suitableampoules or vials. Any suitable additive conventionally used in the artmay be added, such as tonicity agents, preservatives, antioxidants, etc.

In a further aspect the present invention relates to a method ofpreparing a compound of the invention as described in the following.

Methods of Preparation of the Compounds of the Invention

The compounds of the invention may be prepared as follows:

Method 1 (for compounds of formula IA) Alkylating an amine of formulaIII with an alkylating derivative of formula II:

where R¹-R¹³ are as defined herein, and L is a leaving group such ase.g. halogen, mesylate or tosylate;

whereupon the compound of formula IA is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 2 (for compounds of formula IA) Reduction of an amide derivativeof formula IV:

where R¹-R¹³ are as defined herein;

whereupon the compound of formula IA is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 3 (for compounds of formula IA, also for compounds of formula IBwhen R¹²≠hydrogen) Reacting an indole of formula V with a reagent offormula VI by the use of a catalyst:

where R¹-R¹³ are as defined herein;

whereupon the compound of formula IA or the compound of formula IB whenR¹²≠hydrogen is isolated as the free base or a salt such as apharmaceutically acceptable acid addition salt thereof.

Method 4 (for compounds of formula IC) Reduction of an amide derivativeof formula VII:

where R¹-R¹³ are as defined herein;

whereupon the compound of formula IC is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 5 (for compounds of formula ID) Reduction of an amide derivativeof formula VIII:

where R¹-R¹³ are as defined herein;

whereupon the compound of formula ID is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 6 (for compounds of formula IE) Reduction of an amide derivativeof formula IX:

where R¹-R¹³ are as defined herein;

whereupon the compound of formula IE is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 7 (for compounds of formula IF) Reduction of an amide derivativeof formula X:

where R¹-R¹³ are as defined herein;

whereupon the compound of formula IF is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 8 (for compounds of formula IB with R¹²=hydrogen) Reduction of anamide derivative of formula XI:

where R¹-R¹³ are as defined herein;

whereupon the compound of formula IB is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 9 (for compounds of formula IC with R²=hydrogen) Deprotection ofa compound of formula XII:

where R¹, R³-R¹³ are as defined herein and R′ is a protection group suchas a carbamate (such as methyl-, ethyl-, tert-butyl-, allyl-, orbenzyl-carbamate);

whereupon the compound of formula IC is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 10 (for compounds of formula ID with R²=hydrogen) Deprotection ofa compound of formula XIII:

where R¹, R³-R¹³ are as defined herein and R′ is a protection group suchas a carbamate (such as methyl-, ethyl-, tert-butyl-, allyl-, orbenzyl-carbamate); whereupon the compound of formula ID is isolated asthe free base or a salt such as a pharmaceutically acceptable acidaddition salt thereof.

Method 11 (for compounds of formula IE with R²=hydrogen) Deprotection ofa compound of formula XIV:

where R¹, R³-R¹³ are as defined herein and R′ is a protection group suchas a carbamate (such as methyl-, ethyl-, tert-butyl-, allyl-, orbenzyl-carbamate);

whereupon the compound of formula IE is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

Method 12 (for compounds of formula IF with R²=hydrogen) Deprotection ofa compound of formula XV:

where R¹, R³-R¹³ are as defined herein and R′ is a protection group suchas a carbamate (such as methyl-, ethyl-, tert-butyl-, allyl-, orbenzyl-carbamate);

whereupon the compound of formula IF is isolated as the free base or asalt such as a pharmaceutically acceptable acid addition salt thereof.

The alkylation according to method 1 is conveniently performed in anorganic solvent such as a suitably boiling alcohol or ketone, preferablyin the presence of an organic or inorganic base (potassium carbonate,diisopropylethylamine or triethylamine) at reflux temperature.Alternatively, the alkylation can be performed at a fixed temperature,which is different from the boiling point, in one of the above-mentionedsolvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO), orN-methylpyrrolidin-2-one (NMP), preferably in the presence of a base.The alkylating derivatives of formula II can be derived from thecorresponding benzylic alcohols which in turn are synthesised from thecorresponding benzoic acids by standard reduction methods e.g. by theuse of lithium aluminium hydride. The corresponding benzoic acids can besynthesised by methods analogous to those described in e.g. Hamel, P.;Girard, M.; Tsou, N. N.; J. Heterocycl. Chem.; 36, 1999, 643-652. Theamines of formula III are commercially available.

The reduction according to method 2 is performed by standard literaturemethods i.e. by the use of a reducing agent like borane, alane orlithium aluminium hydride. Amides of the formula V can be prepared bycoupling of the corresponding benzoic acids (synthesised by methodsanalogous to those described in e.g. Hamel, P.; Girard, M.; Tsou, N. N.;J. Heterocycl. Chem.; 36, 1999, 643-652 and Hamel, P.; Zajac, N.;Atkinson, J. G.; Girard, Y.; J. Org. Chem.; 59; 21; 1994; 6372-6377)with an amine of formula III by standard methods e.g. via the carboxylicacid chloride or activated esters or by the use of carboxylic acids incombination with a coupling reagent such as e.g. dicyclohexylcarbodiimide.

The reaction in method 3 can be performed by reacting aN-alkyl-2,3-dihydro-benzo [d]isothiazole of formula VI with an indole offormula V in the presence of an activating agent like e.g. an lewis acidor e.g. an oxidising agent like e.g. N-chlorosuccinimide.N-Alkyl-2,3-dihydro-benzo[d]isothiazoles of formula VI can be preparedby methods analogous to those described in the literature e.g. Hoffmann,R. W.; Goldmann, S.; Chem. Ber. 111, 1978, 2716-2725 and Kanakarajan,K.; Meier, H.; Angew. Chem. 96, 1984, 220. Indoles of formula V areeither commercially available or can be prepared by standard methods asdescribed in standard works like e.g. Houben-Weyl, Methoden derorganischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag,Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York.

The reduction according to method 4 is performed by standard literaturemethods i.e. by the use of a reducing agent like borane, alane orlithium aluminium hydride. Amides of the formula VII can be prepared bycoupling of the corresponding 2-mercapto-benzamides (synthesised byreduction of the corresponding 2,2′-dithiobenzamides analogous to thosedescribed in e.g. Elworthy, T. R.; Ford, A. P. D. W.; Bantle, G. W.;Morgans, D. J.; Ozer, R. S.; et al. J. Med. Chem. 40, 1997, 2674-2687)with a 4-halo- or 4-pseudohalo indole by methods analogous to thosedescribed in the literature e.g. Schopfer, U.; Schlapbach, A.Tetrahedron; 57, 2001, 3069-3073, where “halo” is either bromo or iodoor “pseudohalo” is e.g. triflate or nonaflate. When R¹³=hydrogen informula VII, then this position is protected prior to the couplingreaction and deprotected after the coupling reaction according tostandard literature procedures with standard protection groups, e.g. a4-methyl-phenyl-sulfonyl group or a tert-butoxy-carbonyl group.

The reduction according to method 5 is performed by standard literaturemethods i.e. by the use of a reducing agent like borane, alane orlithium aluminium hydride. Amides of the formula VIII can be prepared bycoupling of the corresponding 2-mercapto-benzamides (synthesised byreduction of the corresponding 2,2′-dithiobenzamides analogous to thosedescribed in e.g. Elworthy, T. R.; Ford, A. P. D. W.; Bantle, G. W.;Morgans, D. J.; Ozer, R. S.; et al. J. Med. Chem. 40, 1997, 2674-2687)with a 5-halo- or 5-pseudohalo indole by methods analogous to thosedescribed in the literature e.g. Schopfer, U.; Schlapbach, A.Tetrahedron; 57, 2001, 3069-3073, where “halo” is either bromo or iodoor “pseudohalo” is e.g. triflate or nonaflate. When R¹³=hydrogen informula VIII, then this position is protected prior to the couplingreaction and deprotected after the coupling reaction according tostandard literature procedures with standard protection groups, e.g. a4-methyl-phenyl-sulfonyl group or a tert-butoxy-carbonyl group.

The reduction according to method 6 is performed by standard literaturemethods i.e. by the use of a reducing agent like borane, alane orlithium aluminium hydride. Amides of the formula IX can be prepared bycoupling of the corresponding 2-mercapto-benzamides (synthesised byreduction of the corresponding 2,2′-dithiobenzamides analogous to thosedescribed in e.g. Elworthy, Todd R.; Ford, Anthony P. D. W.; Bantle,Gary W.; Morgans, David J.; Ozer, Rachel S.; et al. J. Med. Chem. 40,1997, 2674-2687) with a 6-halo- or 6-pseudohalo indole by methodsanalogous to those described in the literature e.g. Schopfer, U.;Schlapbach, A. Tetrahedron; 57, 2001, 3069-3073, where “halo” is eitherbromo or iodo or “pseudohalo” is e.g. triflate or nonaflate. WhenR¹³=hydrogen in formula IX, then this position is protected prior to thecoupling reaction and deprotected after the coupling reaction accordingto standard literature procedures with standard protection groups, e.g.a 4-methyl-phenyl-sulfonyl group or a tert-butoxy-carbonyl group.

The reduction according to method 7 is performed by standard literaturemethods i.e. by the use of a reducing agent like borane, alane orlithium aluminum hydride. Amides of the formula X can be prepared bycoupling of the corresponding 2-mercapto-benzamides (synthesised byreduction of the corresponding 2,2′-dithiobenzamides analogous to thosedescribed in e.g. Elworthy, T. R.; Ford, A. P. D. W.; Bantle, G. W.;Morgans, D. J.; Ozer, R. S.; et al. J. Med. Chem. 40, 1997, 2674-2687)with a 7-halo- or 7-pseudohalo indole by methods analogous to thosedescribed in the literature e.g. Schopfer, U.; Schlapbach, A.Tetrahedron; 57, 2001, 3069-3073, where “halo” is either bromo or iodoor “pseudohalo” is e.g. triflate or nonaflate. When R¹³=hydrogen informula X, then this position is protected prior to the couplingreaction and deprotected after the coupling reaction according tostandard literature procedures with standard protection groups, e.g. a4-methyl-phenyl-sulfonyl group or a tert-butoxy-carbonyl group.

The reduction according to method 8 is performed by standard literaturemethods i.e. by the use of a reducing agent like borane, alane orlithium aluminium hydride. Amides of the formula X can be prepared byacidic rearrangement (e.g. treatment in a solution of trifluoroaceticacid) of amides of formula IV analogous to methods described in theliterature (Hamel, P.; Girard, M.; Tsou, N. N.; J. Heterocyclic Chem.36, 1999, 643-652; Hamel, P.; Girard, Y.; Atkinson, J. G.; J. Org. Chem.57, 1992; 2694-2699).

The deprotection according to method 9 can be performed by standardtechniques, known to the persons skilled in the art and detailed in thetextbook Protective Groups in Organic Synthesis Greene, T. W.; Wuts, P.G. M. Wiley Interscience, (1991) ISBN 0471623016. The protected aminecan be prepared in a similar manner as described in the literature byreaction of properly substituted (2-mercapto-benzyl)-methyl-carbamicacid ester with properly substituted 4-halo indole or 4-pseudohaloindole, where “halo” is either bromo or iodo and “pseudohalo” is e.g.triflate or nonaflate, according to Schopfer, H.; Schlapbach, U.;Tetrahedron 2001, 57, 3069-3073. When R¹³=hydrogen in formula XII, thenthis position is protected prior to the coupling reaction anddeprotected after the coupling reaction according to standard literatureprocedures with standard protection groups, e.g. a4-methyl-phenyl-sulfonyl group or a tert-butoxy-carbonyl group. Theproperly substituted (2-mercapto-benzyl)-methyl-carbamic acid ester canbe prepared from the properly substituted(2-bromo-benzyl)-methyl-carbamic acid ester or properly substituted(2-iodo-benzyl)-methyl-carbamic acid ester in a palladium catalysedcoupling reaction with a trialkylsilane thiol with subsequentdesilylation with a fluoride donor such as tetrabutylammonium fluoride(Winn, M.; et al. J. Med. Chem. 2001, 44, 4393-4403).

The deprotection according to method 10 can be performed as described inmethod 9. The protected amine can be prepared from the properlysubstituted (2-mercapto-benzyl)-methyl-carbamic acid ester and theproperly substituted 5-halo indole or 5-pseudohalo indole, where “halo”is either bromo or iodo and “pseudohalo” is e.g. triflate or nonaflate,as described in method 9. When R¹³=hydrogen in formula XIII, then thisposition is protected prior to the coupling reaction and deprotectedafter the coupling reaction according to standard literature procedureswith standard protection groups, e.g. a 4-methyl-phenyl-sulfonyl groupor a tert-butoxy-carbonyl group.

The deprotection according to method 11 can be performed as described inmethod 9. The protected amine can be prepared from the properlysubstituted (2-mercapto-benzyl)-methyl-carbamic acid ester and theproperly substituted 6-halo indole or 6-pseudohalo indole, where “halo”is either bromo or iodo and “pseudohalo” is e.g. triflate or nonaflate,as described in method 9. When R¹³=hydrogen in formula XIV, then thisposition is protected prior to the coupling reaction and deprotectedafter the coupling reaction according to standard literature procedureswith standard protection groups, e.g. a 4-methyl-phenyl-sulfonyl groupor a tert-butoxy-carbonyl group.

The deprotection according to method 12 can be performed as described inmethod 9. The protected amine can be prepared from the properlysubstituted (2-mercapto-benzyl)-methyl-carbamic acid ester and theproperly substituted 7-halo indole or 7-pseudohalo indole, where “halo”is either bromo or iodo and “pseudohalo” is e.g. triflate or nonaflate,as described in method 9. When R¹³=hydrogen in formula XV, then thisposition is protected prior to the coupling reaction and deprotectedafter the coupling reaction according to standard literature procedureswith standard protection groups, e.g. a 4-methyl-phenyl-sulfonyl groupor a tert-butoxy-carbonyl group.

The invention disclosed herein is further illustrated by the followingnon-limiting examples.

EXAMPLES

General Methods

Analytical LC-MS data were obtained on a PE Sciex API 150EX instrumentequipped with photoionization (APPI) ion source and ShimadzuLC-8A/SLC-10A LC system. The LC conditions (Symmetry C18 column 4.6×30mm with a particle size of 3.5 μm) were linear gradient elution witheluents A (water containing 0.05% TFA) and B (acetonitrile containing 5%water and 0.035% TFA). Gradient (time[min]/% B): (0.00/10.0);(4.00/100.0); (4.10/10.0); (5.00/10.0) with 2 μL/min. Purity wasdetermined by integration of the UV trace (254 nm) and ELS (SEDERE SEDEX55 with Heto CBN 8-30 cooling bath). The retention times, R_(t), areexpressed in minutes.

Mass spectra were obtained by an alternating scan method to givemolecular weight information. The molecular ion, MH+, was obtained atlow orifice voltage (5V) and fragmentation at high orifice voltage(100V).

Preparative LC-MS-separation was performed on the same instrument. TheLC conditions (Symmetry C18 column 10×50 mm) were linear gradientelution with eluents A (water containing 0.05% TFA) and B (acetonitrilecontaining 5% water and 0.035% TFA): (time[min]/% B): (0.00/20.0);(7.00/100.0); (7.10/20.0); (8.00/20.0) with 5.7 mL/min Fractioncollection was performed by split-flow MS detection.

For column chromatography silica gel of formula Kieselgel 60, 230-400mesh ASTM was used. For ion-exchange chromatography (SCX, 1 g, VarianMega Bond Elut®, Chrompack cat. No. 220776) was used. Prior to use theSCX-columns were pre-conditioned with 10% solution of acetic acid inmethanol (3 mL).

Preparation of Intermediates

Example 1 2-(1H-Indol-3-ylsulfanyl)-N,N-dimethyl benzamide

N,N,N′,N′-Tetramethyl-2,2′-dithiodibenzamide (Elworthy, Todd R.; Ford,Anthony P. D. W.; Bantle, Gary W.; Morgans, David J.; Ozer, Rachel S.;et al. J. Med. Chem. 40, 1997, 2674-2687) (12.80 g, 35.5 mmol) wasdissolved in 1,2-dichloroethane (200 mL) under Ar, and sulfurylchloride(2.9 mL, 4.84 g, 35.9 mmol) was carefully added with stirring under Ar.The reaction mixture was stirred for 15 min at room temperature and theresulting solution was added slowly (dropwise) to an icecold solution(0° C.) of indole (8.4 g, 71.7 mmol) in dry DMF (180 mL) under Ar. Themixture was stirred at 0° C. under Ar for 2.5 hours and then quenched byaddition of water (180 mL) and sat. aqueous NaHCO₃ (150 mL). To theresulting emulsion was added ethyl acetate (250 mL). The organic phaseswere combined and washed with brine (100 mL). The water phase wasfurther extracted with ethyl acetate (2×100 mL) and the combined organicphases were washed with brine and dried over MgSO₄ and evaporated invacuo to a dark orange oil which crystallized upon standing. The productwas purified and isolated by recrystallisation (acetonitrile) to give5.53 g (26%) crystalline product (m.p. 195.6-197.6° C.). From themotherliq. was further 4.45 g (21%) product isolated (m.p. 194.3-196.4°C.).

The following compounds were prepared in a similar way:

-   2-(4-Chloro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(4-Fluoro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(4-Fluoro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(5-Fluoro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(5-Chloro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   N,N-Dimethyl-2-(7-methyl-1H-indol-3-ylsulfanyl)benzamide-   2-(5-Methoxy-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(6-Fluoro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(6-Chloro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   N,N-Dimethyl-2-(2-methyl-1H-indol-3-ylsulfanyl)benzamide-   2-(6-Hydroxy-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(7-Methoxy-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   N,N-Dimethyl-2-(4-methyl-1H-indol-3-ylsulfanyl)benzamide-   N,N-Dimethyl-2-(7-nitro-1H-indol-3-ylsulfanyl)benzamide-   2-(4-Hydroxy-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(4-Cyano-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(6-Cyano-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(7-Chloro-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   2-(6-Methoxy-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   N,N-Dimethyl-2-(1-methyl-1H-indol-3-ylsulfanyl)benzamide-   2-(4-Methoxy-1H-indol-3-ylsulfanyl)-N,N-dimethyl benzamide-   N,N-Dimethyl-2-(6-methyl-1H-indol-3-ylsulfanyl)benzamide

Example 2 2-(1H-Indol-3-ylsulfanyl)-N-methyl benzamide

Carbonyldiimidazole (11 mmol) was added to a solution of2-(1H-indol-3-ylsulfanyl)benzoic acid (Hamel, P.; Girard, M.; Tsou, N.N.; J. Heterocycl. Chem. 36, 1999, 643-652) (10 mmol) in dry THF (200mL) and refluxed for 60 minutes under argon. Methyl amine (1M in THF; 40ml) was added slowly to the reaction mixture and the mixture was stirredat room temperature for 16 hours. The mixture was evaporated in vacuoand the product purified by column chromatography on silica gel usingethyl acetate as an eluent.

The following compounds were prepared in a similar way:

-   2-(5-Fluoro-1H-indol-3-ylsulfanyl)-N-methyl benzamide-   2-(6-Fluoro-1H-indol-3-ylsulfanyl)-N-methyl benzamide-   2-(2-Methyl-1H-indol-3-ylsulfanyl)-N-methyl benzamide-   2-(4-Methyl-1H-indol-3-ylsulfanyl)-N-methyl benzamide-   2-(4-Chloro-1H-indol-3-ylsulfanyl)-N-methyl benzamide

Example 3 (2-mercapto-benzyl)-methyl-carbamic acid tert-butyl ester

(2-Iodo-benzyl)-methyl-carbamic acid tert-butyl ester (5.0 g, 14.4 mmol)in dry toluene (30 mL) was placed in two Emrys Optimizer EXP 20 mLtubes. To each tube tris(dibenzylideneacetone)dipalladium (66 mg, 0.072mmol), bis(2-diphenylphosphinophenyl)ether (78 mg, 0.14 mmol),triisopropylsilanethiol (1.44 g, 7.56 mmol) and sodium tert-butoxide(900 mg, 9.36 mmol) were added sequentially. The tubes were sealed andsubjected to microwave heating at 160° C. for 15 minutes. After coolingthe mixture, the product was eluted through a plug of silica with ethylacetate-heptane (1:10) to give 5.2 g (88%) ofmethyl-(2-triisopropylsilanylsulfanyl-benzyl)-carbamic acid tert-butylester. This product was dissolved in THF (70 mL) and cooled to 0° C.Tetrabutylammonium fluoride trihydrate (4.21 g, 13.3 mmol) dissolved inTHF (40 mL) was added dropwise at 0° C. and the mixture was stirred atthis temperature for 15 minutes. The crude mixture was poured onto aplug of silica gel and the product was eluted with ethyl acetate-heptane(1:2) to give 3.2 g (100%) of (2-mercapto-benzyl)-methyl-carbamic acidtert-butyl ester contaminated with traces of triisopropylsilanefluoride.

Example 4 Compounds of the Invention of Formula I

Synthesis of

1. [2-(1H-Indol-3-ylsulfanyl)benzyl]dimethyl amine

2-(1H-Indol-3-ylsulfanyl)-N,N-dimethyl benzamide (1 mmol) was dissolvedin dry tetrahydrofuran (30 mL). To the mixture was added 3 mL 1 M boranein tetrahydrofuran and the mixture was stirred at room temperature for24 hours. Methanol (5 mL) was added and the mixture stirred at roomtemperature for 30 min and then evaporated in vacuo. The mixture wasredissolved in ethyl acetate (100 mL) and washed with saturated sodiumhydrogen carbonate (20 mL), dried over anhydrous MgSO₄ and evaporated invacuo. The product was crystallized as an oxalate salt by dissolution inacetone and addition of one equivalent of oxalic acid.

The Following Compounds were Prepared in a Similar Way and AnalyticalData are Shown in Table 1:

-   2. [2-(5-cyano-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   3. [2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   4. [2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   5. [2-(5-Fluoro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   6. [2-(5-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   7. Dimethyl-[2-(7-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   8. [2-(7-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   9. [2-(5-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   10. [2-(6-Fluoro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   11. [2-(6-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   12. Dimethyl-[2-(2-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   13. Dimethyl-[2-(6-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   14. [2-(4-cyano-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   15. Dimethyl-[2-(1-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   16. Dimethyl-[2-(4-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   17. Dimethyl-[2-(4-hydroxy-1H-indol-3-ylsulfanyl)benzyl]amine-   18. [2-(6-cyano-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   19. [2-(7-Chloro-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   20. [2-(6-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine-   21. [2-(4-Methoxy-1H-indol-3-ylsulfanyl)benzyl]dimethyl amine

Example 5 Compounds of Formula I

Synthesis of

22. [2-(1H-Indol-3-ylsulfanyl)benzyl]methyl amine

2-Methyl-2,3-dihydro-benzoisothiazole (VI) (Hoffmann, R. W.; Goldman, S.Chem. Ber. 111, 1978, 2716-2725) (75 mg, 0.50 mmol) was dissolved in THF(1 mL) and added to indole (V) (140 mg, 0.60 mmol) under Ar.Tricloroacetic acid (90 mg, 0.55 mmol) was added and the reactionmixture was stirred at room temperature for 16 hours. 2 mL 1N NaOH (aq)was added. Extraction with ethyl acetate (2×10 mL) and purification byflash chromatography on silica gel (eluent: ethyl acetate then ethylacetate/methanol/triethylamine) gave 88 mg[2-(1H-Indol-3-ylsulfanyl)benzyl]methyl amine (67% yield).

The Following Compounds were Prepared in a Similar Way and AnalyticalData are Shown in Table 1:

-   23. [2-(6-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   24. [2-(5-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   25. Methyl-[2-(4-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   26. [2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   27. Methyl-[2-(2-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   28. [2-(5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   29. Methyl-[2-(5-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   30. Methyl-[2-(7-methyl-1H-indol-3-ylsulfanyl)benzyl]amine-   31. [2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   32. [2-(7-Ethyl-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   33. [2-(6-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   34. [2-(5-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   35. [2-(6-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   36. [2-(5-Methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]methyl    amine-   37. [2-(5,6-Dimethoxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   38. [2-(6-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   39. Methyl-[2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]amine-   40. [2-(4,7-Dimethoxy-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   41. [2-(5-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   42. [2-(4-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   43. [2-(5-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   44. [2-(7-Methoxy-1H-indol-3-ylsulfanyl)benzyl]methyl amine-   45. [5-Chloro-2-(1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   46. Methyl-[2-(6-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzyl]amine-   47. [5-Hydroxy-2-(1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   48. [2-(4-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   49. [2-(7-Chloro-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   50. [2-(5-Iodo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   51. [2-(6-Cyano-1H-indol-3-ylsulfanyl)-benzyl]methyl amine-   52. [2-(1H-Indol-3-ylsulfanyl)-5-methyl-benzyl]methyl amine-   53. [2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]methyl amine-   54.    [2-(5,6-Dimethoxy-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   55.    [5-Fluoro-2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]-methyl-amine-   56.    [5-Fluoro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   57.    [2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   58.    [2-(7-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   59.    [5-Fluoro-2-(6-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   60.    [5-Fluoro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   61. [2-(4-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   62.    3-(4-Fluoro-2-methylaminomethyl-phenylsulfanyl)-2-methyl-1H-indol-4-ol-   63. 3-(4-Fluoro-2-methylaminomethyl-phenylsulfanyl)-1H-indol-6-ol-   64.    [5-Fluoro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   65.    [5-Fluoro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   66.    [2-(6-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   67.    [2-(5-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   68.    [5-Fluoro-2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   69.    [5-Fluoro-2-(5-methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   70. [2-(5-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   71.    [5-Fluoro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   72. [2-(6-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine-   73.    [5-Fluoro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   74.    [5-Fluoro-2-(6-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   75.    [5-Fluoro-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   76.    [5-Fluoro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   77.    [5-Fluoro-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   78.    [5-Fluoro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   79.    [5-Fluoro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   80.    [5-Fluoro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   81.    [5-Chloro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   82.    [5-Chloro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   83.    [5-Chloro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   84.    [5-Chloro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   85.    [5-Chloro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   86.    [5-Chloro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   87.    [5-Chloro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   88.    [5-Chloro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   89.    [2-(5-Fluoro-2-methyl-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   90.    Methyl-[5-methyl-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-amine-   91. [2-(7-Ethyl-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   92.    [2-(6-Methoxy-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   93.    Methyl-[5-methyl-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-amine-   94.    [2-(4-Methoxy-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   95. [2-(6-Bromo-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   96.    [2-(6-Fluoro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   97.    [2-(4-Fluoro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   98. 3-(4-Methyl-2-methylaminomethyl-phenylsulfanyl)-1H-indol-6-ol-   99.    [5-Chloro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   100.    [2-(6-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   101.    [2-(5-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine-   105.    [4-Chloro-2-(6-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   106.    [4-Chloro-2-(2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   107.    [4-Chloro-2-(5-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   108.    [4-Chloro-2-(7-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   109.    [4-Chloro-2-(4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   110.    [4-Chloro-2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   111.    [4-Chloro-2-(6-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   112.    [4-Chloro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   113.    [4-Chloro-2-(7-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   114.    [4-Chloro-2-(7-ethyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   115.    [4-Chloro-2-(5-methoxy-4-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   116.    [4-Chloro-2-(5-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   117.    [4-Chloro-2-(6-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   118.    [4-Chloro-2-(7-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   119.    [4-Chloro-2-(4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   120.    [4-Chloro-2-(5-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   121.    [4-Chloro-2-(6-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   122.    [4-Chloro-2-(4-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   123.    [4-Chloro-2-(7-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   124. [4-Chloro-2-(1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   125.    [4-Chloro-2-(1-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   126.    [4-Chloro-2-(3-methyl-1H-indol-2-ylsulfanyl)-benzyl]-methyl-amine-   127.    [4-Chloro-2-(5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   129.    [2-(5-Fluoro-4-methoxy-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   130. [2-(4,5-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   131. [2-(4,6-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   132. 3-(2-Methylaminomethyl-phenylsulfanyl)-1H-indol-4-ol-   134. [2-(5,6-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine-   135. 6-Fluoro-3-(2-methylaminomethyl-phenylsulfanyl)-1H-indol-5-ol-   136.    [2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine

Example 6 Compounds of formula I

Synthesis of

102. 5-Fluoro-3-(2-piperidin-1-ylmethyl-phenylsulfanyl)-1H-indole

6 mL conc. H₂SO₄ was added to 2,2′-dithiodibenzoic acid (20 g, 65.3mmol) in 150 mL methanol. The reaction mixture was refluxed for threedays, cooled to room temperature and neutralized with sat. aqueousNaHCO₃. Methanol was removed in vacuo. The residue was extracted withethyl acetate. The organic phase was washed with brine, dried with MgSO₄and concentrated in vacuo to give 17.8 g dimethyl 2,2′-dithiodibenzoicacid ester (53.2 mmol, 82%). 1.20 mL Sulfurylchloride (15 mmol) wasadded to 5.00 g dimethyl 2,2′-dithiodibenzoic acid ester (15 mmol) in 40mL dry 1,2-dichloroethane under Ar at 0° C. The reaction mixture wasstirred 15 min at room temperature and added to 4.10 g fluoro-1H-indole(30.3 mmol) in 50 mL dry THF under Ar. The reaction mixture was stirredfor 2 hours at room temperature and then quenched by addition of sat.aqueous NaHCO₃. Ethyl acetate was added, the two phases were separatedand the organic phase was washed with brine, dried with MgSO₄ andconcentrated in vacuo. 8.30 g 2-(5-Fluoro-1H-indol-3-ylsulfanyl)-benzoicacid methyl ester (27.5 mmol, 92%) was isolated after flashchromatography on silica gel. 4.15 g2-(5-Fluoro-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (13.8 mmol)in 50 mL dry THF was added dropwise to 0.58 g LiAlH₄ (15.4 mmol) in 20mL dry diethyl ether at 0° C. 150 mL dry THF was added and the reactionmixture was stirred 16 hours at room temperature. The reaction wasquenched with 1 mL water and 1 mL 2N NaOH. The reaction mixture wasstirred for 1 hour, then 2.5 mL water was added and stirring wascontinued for another hour. The mixture was filtered, dried with MgSO₄and concentrated in vacuo to give 3.00 g2-(5-fluoro-1H-indol-3-ylsulfanyl)-phenyl]-methanol (11.0 mmol, 80%).0.275 g p-Toluenesulfonylchloride (1.44 mmol) was added to 0.375 g2-(5-fluoro-1H-indol-3-ylsulfanyl)-phenyl]-methanol (1.37 mmol) in 5 mLdry THF at 0° C. The reaction mixture was stirred 2 hours at 0° C. andthen added to 2.75 mmol piperidine in 10 mL dry THF and stirred 16 hoursat room temperature. Water and ethyl acetate were added to the reactionmixture. The two phases were separated and the organic phase was washedwith brine, dried with MgSO₄ and concentrated in vacuo.5-Fluoro-3-(2-piperidin-1-ylmethyl-phenylsulfanyl)-1H-indole wasisolated after flash chromatography.

The Following Compounds were Prepared in a Similar Way and AnalyticalData are Shown in Table 1:

-   103. 5-Fluoro-3-(2-morpholin-4-ylmethyl-phenylsulfanyl)-1H-indole-   104. 5-Fluoro-3-(2-pyrrolidin-1-ylmethyl-phenylsulfanyl)-1H-indole

Example 7 Compounds of Formula I

Synthesis of

128. 2-(5-Fluoro-1H-indol-3-ylsulfanyl)-benzylamine

4.50 g NaBH₄ (119 mmol) was added in portions to 7.50 g allyl bromide(62.0 mmol) and 8.35 g 2,2′-dithiodibenzamide (27.4 mmol, prepared from2,2′-dithiodibenzoic acid via 2,2′-dithiodibenzoic acid chloride) in 80mL methanol at 0° C. The reaction mixture was stirred 1 hour at roomtemperature. 50 mL 1N HCl was added and stirring was continued 1 hour.Methanol was removed in vacuo. The residue was extracted with ethylacetate. The organic phase was washed with brine, dried with MgSO₄ andconcentrated in vacuo to give 10.0 g 2-allylsulfanyl-benzamide (51.7mmol, 94%). 2.1 g LiAlH₄ (55 mmol) was added to 6.0 g2-allylsulfanyl-benzamide (31 mmol) in 50 mL dry THF at 0° C. Thereaction mixture was stirred for 16 hours at room temperature. Thereaction was quenched with 4 mL water and 3 mL 2N NaOH. The reactionmixture was stirred for 1 hour, then 9 mL water was added and stirringwas continued for another hour. The mixture was filtered, dried withMgSO₄ and concentrated in vacuo to give 5.05 g2-allylsulfanyl-benzylamine (28.2 mmol, 91%). 2.05 g Di-tert-butyldicarbonate (9.37 mmol) was added to 1.40 g 2-allylsulfanyl-benzylamine(7.81 mmol) and a catalytic amount of N,N-dimethyl-4-amino pyridine in20 mL THF. The reaction mixture was stirred for 15 minutes at roomtemperature. 10 mL 20% citric acid was added and the reaction mixturewas stirred for 30 minutes. The reaction mixture was extracted withethyl acetate, the two phases were separated and the organic phase waswashed with brine, dried with MgSO₄ and concentrated in vacuo to give(2-allylsulfanyl-benzyl)-carbamic acid tert-butyl ester in quantitativeyield. 0.70 g NaIO₄ (3.3 mmol) in 20 mL water was added to 0.75 g(2-allylsulfanyl-benzyl)-carbamic acid tert-butyl ester (2.7 mmol) in 20mL methanol and stirred for 2 hours at room temperature. The reactionmixture was filtered and methanol was removed in vacuo. The residue wasextracted with ethyl acetate. The organic phase was washed with brine,dried with MgSO₄ and concentrated in vacuo. The residue was redissolvedin 5 mL THF and added to 0.50 g fluoro-1H-indole (3.7 mmol) and 0.65 gtrichloro acetic acid (4.0 mmol) in 5 mL THF and stirred for 16 hours at50° C. Sat. aqueous NaHCO₃ and ethyl acetate was added, the two phaseswere separated and the organic phase was washed with brine, dried withMgSO₄ and concentrated in vacuo. The residue was purified by flashchromatography and 0.157 g[2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-carbamic acid tert-butylester (0.42 mmol, 16%) was isolated after recrystallization from ethylacetate/heptane. 8 mL diethyl ether saturated with HCl was added to0.157 g [2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-carbamic acidtert-butyl ester (0.42 mmol) in 8 mL methanol and stirred 16 hours. Thereaction was neutralized with 2N NaOH and extracted with ethyl acetate.The organic phase was washed with brine, dried with MgSO₄ andconcentrated in vacuo to give 0.112 g2-(5-fluoro-1H-indol-3-ylsulfanyl)-benzylamine (98%).

The Following Compound was Prepared in a Similar Way and Analytical Dataare Shown in Table 1:

-   133. 2-(6-Fluoro-1H-indol-3-ylsulfanyl)-benzylamine

Example 8 Compounds of Formula I

Synthesis of

[2-(1H-Indol-5-ylsulfanyl)-benzyl]-methyl-amine

(2-Mercapto-benzyl)-methyl-carbamic acid tert-butyl ester (1.85 g, 7.30mmol) in dry toluene (15 mL) is placed in an Emrys Optimizer EXP 20 mLtube. Tris(dibenzylideneacetone) dipalladium (334 mg, 0.37 mmol),bis(2-diphenylphosphinophenyl)ether (197 mg, 0.37 mmol),tert-butyl-5-bromoindole-1-carboxylate (2.38 g, 8.03 mmol) and potassiumtert-butoxide (860 mg, 7.67 mmol) are added. The reaction vessel issealed and subjected to microwave heating at 160° C. for 15 minutes.Upon cooling the mixture is poured onto a plug of silica and the productis eluted with ethyl acetate-heptane (1:4). 0.67 g (20%) of5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylicacid tert-butyl ester is isolated and used in the next step withoutfurther purification.5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylicacid tert-butyl ester (0.67 g, 1.43 mmol) in methanol (15 mL) anddiethyl ether saturated with hydrochloric acid (15 mL) is stirred atroom temperature for 1 hour and concentrated in vacuo. Ice/water isadded to the remanence and 28% aqueous NaOH is added until pH 9. Theaqueous fraction is extracted with ethyl acetate (3×15 mL). Combinedorganic fractions are dried with MgSO₄ and concentrated in vacuo. Theproduct is purified by silica gel chromatography eluting with ethylacetate-triethyl amine (100:4) followed by ethylacetate-ethanol-triethyl amine (100:5:5). Upon evaporation of thevolatiles, 40 mg (10%) of[2-(1H-indol-5-ylsulfanyl)-benzyl]-methyl-amine is isolated.

The Following Compounds are Prepared in a Similar Way:

-   [2-(1H-Indol-4-ylsulfanyl)-benzyl]-methyl-amine-   [2-(1H-Indol-6-ylsulfanyl)-benzyl]-methyl-amine-   [2-(1H-Indol-7-ylsulfanyl)-benzyl]-methyl-amine

TABLE 1 Measured molecular mass, measured HPLC-retention time (R_(t),min) and UV- and ELSD-purities (%). UV-purity ELSD-purity compound R_(t)(min.) (%) (%) M + H⁺ 1 1.79 97.9 100 283.2 2 1.75 80.6 96.5 307.9 31.83 98.0 97.1 300.8 4 1.91 95.4 98.2 317.1 5 1.83 98.8 99.3 301.1 62.04 99.4 99.1 317.1 7 2.00 97.9 97.4 297.2 8 1.91 96.8 98.3 313.1 91.79 98.9 100 313.2 10 1.91 99.5 100 301.1 11 2.08 96.1 100 316.8 121.87 95.2 99.1 297 13 1.82 98.7 100.0 297.2 14 1.56 95.2 100.0 308 151.88 98.3 100.0 297.1 16 1.81 99.2 100.0 297.1 17 1.49 75.0 91.5 299 181.68 90.0 95.0 308 19 1.96 90.5 95.6 316.8 20 1.77 88.7 96.0 313.1 211.75 87.3 96.9 313 22 1.79 98.5 97.5 269 23 1.95 100 95.4 287 24 1.9499.2 95.8 286.8 25 1.93 97.2 97.0 283.3 26 1.90 98.2 96.3 303 27 1.8797.4 96.8 283.1 28 2.01 97.0 99.1 301.1 29 1.85 98.0 99.9 283 30 1.8998.1 99.8 283 31 1.72 97.9 99.7 286.9 32 2.02 97.9 100 297.1 33 1.7299.5 99.9 299.1 34 1.92 97.7 100 303.1 35 1.97 96.5 99.9 303.1 36 1.8198.8 99.8 313.2 37 1.51 97.7 99.6 329.1 38 2.00 97.5 99.8 346.9 39 1.8780.6 99.0 283.1 40 1.73 84.1 97.9 329.1 41 1.68 87.5 98.5 299.1 42 1.6687.6 99.4 299 43 1.98 93.7 98.7 348.8 44 1.78 93.7 99.3 299.1 45 2.4584.3 85.4 303.3 46 2.05 96.8 100 337.1 47 1.30 93.4 100 285.1 48 1.8392.4 100 348.8 49 1.92 90.6 99.9 303 50 2.00 88.6 99.6 395.1 51 1.6286.1 98.5 293.8 52 1.82 97.0 99.7 283.3 53 2.04 95.9 99.7 283.4 54 1.5673.92 98.05 347.0 55 2.10 74.19 96.08 299.1 56 1.76 78.09 100.00 304.957 1.88 80.25 99.77 320.8 58 1.97 80.83 98.86 320.9 59 2.12 84.31 99.11355.1 60 1.83 86.68 99.15 317.1 61 1.90 87.33 99.75 367.0 62 1.64 88.1099.61 317.0 63 1.41 88.77 99.74 303.1 64 1.83 91.91 100.00 304.8 65 1.7492.27 100.00 317.1 66 2.00 93.20 99.91 321.1 67 1.97 93.68 100.00 320.968 1.92 93.80 99.97 301.0 69 1.85 94.35 100.00 329.1 70 2.00 94.52 99.86367.0 71 1.73 95.29 99.88 317.1 72 2.04 95.56 99.80 367.0 73 1.85 95.67100.00 305.0 74 1.76 96.68 99.95 317.1 75 1.82 97.23 100.00 301.1 761.91 97.71 100.00 301.1 77 1.89 97.73 99.96 301.1 78 1.93 97.79 99.95301.1 79 1.96 98.85 99.95 301.0 80 1.88 99.01 99.86 319.0 81 1.94 86.6599.91 320.9 82 1.85 72.56 100.00 332.8 83 2.03 94.94 99.91 317.1 84 2.0592.54 99.90 317.1 85 1.85 86.79 99.70 332.9 86 1.95 82.70 99.69 333.0 871.97 85.03 99.85 320.9 88 1.99 88.12 100.00 335.0 89 1.95 99.44 100.00315.1 90 1.97 98.16 100.00 297.2 91 2.12 95.13 99.74 311.3 92 1.83 93.40100.00 313.1 93 1.78 92.78 98.90 297.0 94 1.79 92.77 100.00 313.1 952.11 90.80 100.00 363.0 96 1.94 89.78 99.94 301.1 97 1.84 87.54 100.00301.0 98 1.49 87.12 99.49 299.1 99 1.51 86.97 100.00 318.9 100 2.0785.51 98.57 317.1 101 2.04 81.67 94.01 317.0 102 2.00 82.20 80.30 341.1103 1.86 90.90 82.40 342.9 104 1.95 90.40 78.70 327.1 105 2.06 92.4999.44 317.1 106 1.96 87.25 98.90 317.0 107 2.03 90.96 99.55 316.8 1082.04 91.97 99.87 316.8 109 2.02 83.80 98.60 317.1 110 1.96 90.04 99.61320.9 111 1.99 97.66 99.69 321.0 112 1.89 88.36 99.15 320.9 113 1.9890.52 99.39 320.9 114 2.18 87.86 99.70 331.0 115 1.97 87.81 99.17 347.0116 1.88 89.22 99.38 333.0 117 1.89 95.36 99.65 332.9 118 1.96 82.3498.84 332.7 119 1.87 90.44 99.82 333.0 120 2.08 89.98 99.57 337.2 1212.13 87.91 99.27 337.1 122 2.00 84.01 98.48 337.2 123 2.11 80.98 99.08337.1 124 1.91 91.92 99.81 303.1 125 2.08 84.95 98.14 316.7 126 2.2570.89 87.20 317.1 127 2.01 83.89 98.73 335.1 128 1.74 88.20 98.40 273.0129 1.77 93.93 99.83 317.1 130 1.78 95.85 99.64 305.0 131 1.80 97.0499.88 305.0 132 1.42 80.84 97.76 285.1 133 1.78 97.33 99.29 273.0 1341.84 97.99 99.48 305.0 135 1.38 92.53 98.73 303.1 136 1.86 93.25 97.20317.0

Example 9 Transporter Binding Assay

Measurements of [³H]-5-HT Uptake into Rat Cortical SynaptosomeS

Whole brains from male Wistar rats (125-225 g), excluding cerebellum,are homogenized in 0.32 M sucrose supplemented with 1 mM nialamid with aglass/teflon homogenizer. The homogenate is centrifuged at 600×g for 10min at 4° C. The pellet is discarded and the supernatant is centrifugedat 20.000×g for 55 min. The final pellet is homogenized (20 sec) in thisassay buffer (0.5 mg original tissue/well). Test compounds (or buffer)and 10 nM [³H]-5-HT are added to 96 well plates and shaken briefly.Composition of assay buffer: 123 mM NaCl, 4.82 mM KCl, 0.973 mM CaCl₂,1.12 mM MgSO₄, 12.66 mM Na₂HPO₄, 2.97 mM NaH₂PO₄, 0.162 mM EDTA, 10 mMglucose and 1 mM ascorbic acid. Buffer is oxygenated with 95% 0₂/5% CO₂for 10 min at 37° C. and pH is adjusted 7.4. The incubation is startedby adding tissue to a final assay volume of 0.2 mL. After 15 minincubation with radioligand at 37° C., samples are filtered directly onUnifilter GF/C glass fiber filters (soaked for 1 hour in 0.1%polyethylenimine) under vacuum and immediately washed with 3×0.2 mlassay buffer. Non-specific uptake is determined using citalopram (10 μMfinal concentration). Citalopram is included as reference in allexperiments as dose-response curve.

Measurements of [³H]Noradrenaline Uptake into Rat Cortical Synaptosomes

Fresh cortex from male Wistar rats (125-225 g) are homogenized in 0.4Msucrose with a glass/teflon homogenizer. The homogenate is centrifugedat 600×g for 10 min at 4° C. The pellet is discarded and the supernatantis centrifuged at 20.000×g for 55 min. The final pellet is homogenized(20 sec) in this assay buffer (6 mg original tissue/mL=4 mg/well). Testcompounds (or buffer) and 10 nM [³H]-noradrenaline are added to deep 96well plates and shaken briefly. Composition of assay buffer: 123 mMNaCl, 4.82 mM KCl, 0.973 mM CaCl₂, 1.12 mM MgSO₄, 12.66 mM Na₂HPO₄, 2.97mM NaH₂PO₄, 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. Bufferis oxygenated with 95% 0₂/5% CO₂ for 10 min at 37° C. and pH is adjusted7.4. The incubation is started by adding tissue to a final assay volumeof 1 ml. After 15 min incubation with radioligand at 37° C., samples arefiltered directly on Unifilter GF/C glass fiber filters (soaked for 1hour in 0.1% polyethylenimine) under vacuum and immediately washed with3×1 mL assay buffer. Non-specific uptake is determined using talsupram(10 μM final concentration). Duloxetine is included as reference in allexperiments as dose-response curve.

Results of the experiments showed that the tested compounds of theinvention inhibit the serotonin and norepinephrine reuptake with IC₅₀below 200 nM.

Measurements of [³H]Dopamine Uptake into Rat Synaptosomes

Tissue preparation: male wistar rats (125-250 g) are sacrificed bydecapitated and striatum quickly dissected out and placed in 40 vol(w/v) ice cold 0.40 M sucrose. The tissue is gently homogenised (glassteflon homogeniser) and the P2 fraction is obtained by centrifugation(1000 g, 10 minutes and 40000 g, 20 minutes, 4° C.) and suspended in 560volumes of a modified Krebs-Ringer-phosphate buffer, pH 7.4.

Tissue 0.25 mg/well (140 μl) (original tissue) is mixed with testsuspension. After 5 minutes pre-incubation 12.5 nM 3H-dopamine is addedand the mixture is incubated for 5 minutes at RT.

The incubation is terminated by filtering the samples under vacuumthrough Whatman GF/C filters with a wash of 1 ml buffer. The filters aredried and appropriate scintillation fluid (Optiphase Supermix) is added.After storage for 2 hours in the dark the content of radioactivity isdetermined by liquid scintillation counting. Uptake is obtained bysubtracting the non-specific binding and passive transport measured inthe presence of 100 μM of benztropin. For determination of theinhibition of uptake ten concentrations of drugs covering 6 decades areused.

³H-DA=3,4-(ring-2,5,6-³H)dopamine hydrochloride from New EnglandNuclear, specific activity 30-50 Ci/mmol.

-   Hyttel, Biochem. Pharmacol. 1978, 27, 1063-1068;-   Hyttel, Prog. Neuro-Psychopharmacol. & bil. Psychiat. 1982, 6,    277-295;-   Hyttel & Larsen, Acta Pharmacol. Tox. 1985, 56, suppl. 1, 146-153.

1. A method of treating, excluding prevention, a disease or disordercomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula IA:

wherein; R¹-R² are independently selected from hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, andC₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl or R¹ and R² together with thenitrogen form a 4-7 membered ring containing zero or one double bond,optionally said ring in addition to said nitrogen comprises one furtherheteroatom selected from nitrogen, oxygen and sulphur; R³-R⁷ and R⁹-R¹¹are independently selected from hydrogen, halogen, cyano, nitro,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, amino, C₁₋₆-alk(en/yn)ylamino,di-(C₁₋₆-alk(en/yn)yl)amino, C₁₋₆-alk(en/yn)ylcarbonyl, aminocarbonyl,C₁₋₆-alk(en/yn)ylaminocarbonyl, di-(C₁₋₆-alk(en/yn)yl)aminocarbonyl,hydroxy, C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk (en/yn)ylthio,halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)ylsulfonyl,halo-C₁₋₆-alk(en/yn)ylsulfanyl and C₁₋₆-alk(en/yn)ylsulfonyl; R⁸ ishalogen; and R¹³ is selected from hydrogen or C₁₋₆-alk(en/yn)yl; or apharmaceutically acceptable salt thereof; and said disease or disorderis selected from the group consisting of major depressive disorder,postnatal depression, dysthymia, depression associated with bipolardisorder, depression associated with Alzheimer's, depression associatedwith psychosis, depression associated with Parkinson's, general anxietydisorder, social anxiety disorder, post traumatic stress disorder,obsessive compulsive disorder, panic disorder, panic attacks, specificphobias, social phobia, agoraphobia, fibromyalgia syndrome, overallpain, back pain, shoulder pain, headache, pain while awake and duringdaily activities, attention deficit hyperactivity disorder, and stressurinary incontinence.
 2. The method according to claim 1, wherein saidcompound is selected from the group consisting of:[2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine;[2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl] dimethyl amine;[2-(4-Chloro-1H-indol-3-ylsulfanyl)benzyl]methyl amine;[2-(4-Fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine;[2-(4-Bromo-1H-indol-3-ylsulfanyl)-benzyl]methyl amine;[5-Fluoro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;[2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;[2-(4-Bromo-1H-indol-3-ylsulfanyl)-5-fluoro-benzyl]-methyl-amine;[2-(4-Fluoro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine;[4-Chloro-2-(4-fluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;[4-Chloro-2-(4-chloro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;[2-(4,5-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine;[2-(4,6-Difluoro-1H-indol-3-ylsulfanyl)-benzyl]-methyl-amine; and[2-(4-Chloro-1H-indol-3-ylsulfanyl)-5-methyl-benzyl]-methyl-amine; or apharmaceutically acceptable salt thereof.